Compounds effective as β2-adrenoreceptor agonists as well as PDE4-inhibitors

ABSTRACT

The compounds of formula I in which Ar 1 , A, R6, R7, R8 and Ar 2  have the meanings as given in the description are novel effective bronchial therapeutics

FIELD OF APPLICATION OF THE INVENTION

The invention relates to novel compounds, which act simultaneously asβ2-adrenoreceptor agonist and as PDE4-inhibitor. They are used in thepharmaceutical industry for the production of medicaments.

KNOWN TECHNICAL BACKGROUND

International Patent Applications WO98/31674, WO99/31071 and WO99131090disclose phthalazinone derivatives having selective PDE4 inhibitoryproperties. In the International Patent Application WO94/12461 and inthe European Patent Application EP 0 763 534 3-aryl-pyridazin-6-onerespectively arylalkyl-diazinone derivatives are described as selectivePDE4 inhibitors.

In the International Patent Application WO98/37894 the combinedapplication of PDE-inhibitors with adenylat-cyclase-agonists isdescribed. In this context β-sympathomimetics are mentioned as onepossible example of an adenylat-cyclase-agonist.

In the International Patent Application WO00/12078 is disclosed thecombined application of a PDE4 inhibitor with a beta adrergenicbronchodilator for the treatment of asthma and COPD.

DESCRIPTION OF THE INVENTION

It has now been found that the pyridazinones, which are described ingreater details below, have surprising and particularly advantageousproperties.

The invention thus relates to compounds of the formula I:

in which

-   Ar₁ represents a phenyl radical of formula (Ia) substituted by R1    and R2 or a dihydrobenzofuranyl radical of formula (Ib) substituted    by R3, R4 and R5:    wherein-   R1 is hydroxyl, halogen, 1-4C-alkoxy or 1-4C-alkoxy which is    completely or predominantly substituted by fluorine,-   R2 is hydroxyl, halogen, 1-8C-alkoxy, 3-7C-cycloalkoxy,    3-7C-cycloalkylmethoxy, or 1-4C-alkoxy which is completely or    predominantly substituted by fluorine,-   R3 is 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or    1-4C-alkoxy which is compompletely or predominantly substituted by    fluorine,-   R4 is 1-4C-alkyl and-   R5 is hydrogen or 1-4C-alkyl,    or wherein-   R4 and R5 together and with inclusion of the two carbon atoms, to    which they are bonded, form a spiro-linked 5-, 6- or 7-membered    hydrocarbon ring, optionally interrupted by an oxygen or sulphur    atom,-   R6 and R7 represent independently from one another hydrogen or    1-4C-alkyl, or R6 and R7 together and with inclusion of the two    carbon atoms, to which they are bonded, form a group selected from:-   A represents —C_(m)H_(2m)—Y—X—C_(n)H_(2n)— or    —Y—X—C_(m)H_(2m)—Z—C_(n)H_(2n)—, wherein    -   X represents a bond, —O—(oxygen), —S—(sulfur), —NH—, —C(O)—,        —S(O)₂—, —C(O)—NH—, —NH—C(O)—, —C(S)—NH—, —NH—C(S)—,        —NH—C(O)—NH— or —NH—C(S)—NH—,    -   Y represents a bond, phenylene, 4-8C-cycloalkylene or        azacycloalkylene,    -   Z represents —O—, —S—, —S(O)₂—, —NH—C(O)—, —C(O)—NH—, —NH—C(S)—        or —C(S)—NH—,    -   m is an integer from 0 to 4,    -   n is an integer from 1 to 4,    -   R8 is hydrogen or 1-4C-alkyl,-   Ar₂ represents a 8-hydroxy-1H-quinolin-2-on-5-yl radical or a phenyl    radical substituted by R9, R10 and R11,    wherein-   R9 is hydrogen, halogen, hydroxyl, amino, ureido [—NH—C(O)—NH₂],    formylamino [—NH—C(O)H], 1-4C-alkylcarbonylamino,    di-1-4C-alkylaminocarbonyloxy, tolylcarbonyloxy [—O—C(O)—C₆H₄—CH₃],    hydroxymethyl, 1-4C-alkylcarbonyloxy, 1-4C-alkyl, 1-4C-alkoxy,    1-4C-alkylsulfonylamino, 1-4C-alkylsulfonylmethyl or    1-4C-alkoxy-1-4C-alkyl,-   R10 is hydrogen, halogen, hydroxyl, cyano, trifluoromethyl,    tolylcarbonyloxy [—O—C(O)—C₆H₄—CH₃], hydroxymethyl or    1-4C-alkylcarbonyloxy,-   R11 is hydrogen or halogen,    and the salts of these compounds.

1-4C-alkyl is a straight-chain or branched alkyl radical having 1 to 4carbon atoms. Examples are the butyl, isobutyl, sec-butyl, tert-butyl,propyl, isopropyl, ethyl and methyl radicals.

Halogen within the meaning of the invention is chlorine, bromine orfluorine.

1-4C-alkoxy is a radical which, in addition to the oxygen atom, containsa straight-chain or branched alkyl radical having 1 to 4 carbon atoms.Alkoxy radicals having 1 to 4 carbon atoms which may be mentioned inthis context are, for example, the butoxy, isobutoxy, sec-butoxy,tert-butoxy, propoxy, isopropoxy, ethoxy and methoxy radicals.

3-7C-cycloalkoxy stands for cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy and cycloheptyloxy.

3-7C-cycloalkylmethoxy stands for cyclopropylmethoxy, cyclobutylmethoxy,cyclopentylmethoxy, cyclohexylmethoxy and cycloheptylmethoxy.

1-4C-alkoxy which is completely or predominantly substituted by fluorineis, for example, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy,the 1,2,2-trifluoroethoxy and in particular the1,1,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, thetrifluoromethoxy and the difluoromethoxy radical, of which thedifluoromethoxy radical is preferred. “Predominantly” in this connectionmeans that more than half of the hydrogen atoms of the 1-4C-alkoxy groupare replaced by fluorine atoms.

As spiro-linked 5-, 6- or 7-membered hydrocarbon rings, optionallyinterrupted by an oxygen or sulphur atom, may be mentioned thecyclopentane, cyclohexane, cycloheptane, tetrahydrofuran,tetrahydropyran and the tetrahydrothiophen ring.

Possible radicals —(CH₂)_(m)—, in which m can have the meaning 0, 1, 2,3 or 4 are straight chain or branched divalent alkylene radicals.Examples which may be mentioned are the butylene, isobutylene,sec-butylene, tert-butylene, propylene, isopropylene, ethylene and themethylene radical. The radical —(CH₂)_(m)— represents a bond, if m iszero.

Possible radicals —C_(m)H_(2m)—, in which m can have the meaning 0, 1,2, 3 or 4 are straight chain or branched divalent alkylene radicals.Examples which may be mentioned are the butylene, isobutylene,sec-butylene, tert-butylene, propylene, isopropylene, ethylene and themethylene radical. The radical —C_(m)H_(2m)— represents a bond, if m iszero.

Possible radicals —(CH₂)_(n)—, in which n can have the meaning 1, 2, 3or 4 are straight chain or branched divalent alkylene radicals. Exampleswhich may be mentioned are the butylene, isobutylene, sec-butylene,tert-butylene, propylene, isopropylene, ethylene and the methyleneradical.

Possible radicals —C_(n)H_(2n)—, in which n can have the meaning 1, 2, 3or 4 are straight chain or branched divalent alkylene radicals. Exampleswhich may be mentioned are the butylene, isobutylene, sec-butylene,tert-butylene, propylene, isopropylene, ethylene and the methyleneradical.

An 1-4C-alkylcarbonylamino radical is, for example, the propionylamino[C₃H₇C(O)NH—] and the acetylamino radical [CH₃C(O)NH—].

4-8C-cycloalkylene stands for cyclobutylene, cyclopentylene,cyclohexylene, cycloheptylene or cyclooctylene. Preferred examples are1,4-cyclohexylene and 1,3-cyclohexylene.

Azacycloalkylene stands for a divalent 5-7C-cycloalkylene radical, inwhich one or two of the ring carbon atoms are substituted by a nitrogenatom. Examples which may be mentioned are the 4,1-piperidinylene, the1,4-piperidinylene, the 1,4-homopiperazinylene, the 1,4-piperazinyleneand the 3,1-pyrrolidinylene radical.

Mono- or Di-1-4C-alkylamino radicals contain in addition to the nitrogenatom, one or two of the above-mentioned 1-4C-alkyl radicals. Exampleswhich may be mentioned are the di-1-4C-alkylamino radicals, especiallythe dimethylamino, the diethylamino and the diisopropylamino radical.

Mono- or Di-1-4C-alkylaminocarbonyloxy radicals contain in addition tothe carbonyl group one of the above-mentioned mono- ordi-1-4C-alkylamino radicals. Examples which may be mentioned are theN-methyl- the N,N-dimethyl-, the N-ethyl-, the N-propyl-, theN,N-diethyl- and the N-isopropylaminocarbonyloxy radical.

1-4C-Alkylcarbonyloxy stands for a carbonyloxy group to which one of theabove-mentioned 1-4C-alkyl radicals is bonded. An example is the acetoxyradical [CH₃C(O)—O—].

1-4C-Alkylsulfonylamino is a sulfonylamino (—SO₂—NH—) group to which oneof the above-mentioned 1-4C-alkyl radicals is bonded. An example is themethanesulfonylamino radical (CH₃SO₂NH—).

1-4C-Alkylsulfonylmethyl is a sulfonylmethyl (—SO₂—CH₂—) group to whichone of the above-mentioned 1-4C-alkyl radicals is bonded. An example isthe methanesulfonylmethyl radical (CH₃SO₂CH₂—).

1-4C-Alkoxy-1-4C-alkyl stands for one of the above-mentioned 1-4C-alkylradicals which is substituted by one of the above-mentioned 1-4C-alkoxyradicals. Examples which may be mentioned are the methoxymethyl,methoxyethyl and the butoxyethyl radical.

Ar₂ represents a 8-hydroxy-1H-quinolin-2-on-5-yl radical or a phenylradical substituted by R9, R10 and R11. Examples which may be mentionedfor the phenyl radical substituted by R9, R10 and R11 are phenyl,4-amino-3-chloro-5-cyanophenyl, 4-hydroxy-3-hydroxymethylphenyl,4-amino-3-cyanophenyl, 4-amino-3,5-dichlorophenyl,4-amino-3-chloro-5-trifluoromethylphenyl, 4-aminophenyl,3,4-dihydroxyphenyl, 3,5-dihydroxyphenyl,3,5-bis-tolylcarbonyloxyphenyl, 4-hydroxy-3-ureido-phenyl,3-formylamino-4-hydroxyphenyl, 4-hydroxyphenyl, 3-amino-5-hydroxyphenyl,2-fluorophenyl, 3-amino-5-hydroxymethylphenyl3,5-di-tert-butylcarbonyloxyphenyl, 3,5-di-isopropylcarbonyloxyphenyl,2-chloro-4-hydroxyphenyl, 2-fluoro-4-hydroxyphenyl,3-fluoro-4-hydroxyphenyl, 4-hydroxy-3-methoxyphenyl,4-hydroxy-3-methylsulfonamidophenyl and4-hydroxy-3-methylsulfonylmethylphenyl.

Preferred examples of Ar₂ are 4-amino-3-chloro-5-cyanophenyl,4-hydroxy-3-hydroxymethylphenyl, 4-amino-3-cyanophenyl,4-amino-3-chloro-5-trifluoromethylphenyl and 4-amino-3,5-dichlorophenyl.

Suitable salts for compounds of the formula I—depending onsubstitution—are all acid addition salts or all salts with bases.Particular mention may be made of the pharmacologically tolerableinorganic and organic acids and bases customarily used in pharmacy.Those suitable are, on the one hand, water-soluble and water-insolubleacid addition salts with acids such as, for example, hydrochloric acid,hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid, aceticacid, citric acid, D-gluconic acid, benzoic acid,2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulphosalicylic acid,maleic acid, lauric acid, malic acid, fumaric acid, succinic acid,oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulphonicacid, methanesulphonic acid or 3-hydroxy-2-naphthoic acid, the acidsbeing employed in salt preparation—depending on whether a mono- orpolybasic acid is concerned and depending on which salt is desired—in anequimolar quantitative ratio or one differing therefrom.

On the other hand, salts with bases are—depending on substitution—alsosuitable. As examples of salts with bases are mentioned the lithium,sodium, potassium, calcium, aluminium, magnesium, titanium, ammonium,meglumine or guanidinium salts, here, too, the bases being employed insalt preparation in an equimolar quantitative ratio or one differingtherefrom.

Pharmacologically intolerable salts, which can be obtained, for example,as process products during the preparation of the compounds according tothe invention on an industrial scale, are converted intopharmacologically tolerable salts by processes known to the personskilled in the art.

According to expert's knowledge the compounds of the invention as wellas their salts may contain, e.g. when isolated in crystalline form,varying amounts of solvents. Included within the scope of the inventionare therefore all solvates and in particular all hydrates of thecompounds of formula I as well as all solvates and in particular allhydrates of the salts of the compounds of formula I.

Compounds of the formula I to be emphasized are those in which

-   Ar₁ represents a phenyl radical of formula (Ia) substituted by R1    and R2 or a dihydrobenzofuranyl radical of formula (Ib) substituted    by R3, R4 and R5:    wherein-   R1 is 1-4C-alkoxy or 1-4C-alkoxy which is completely or    predominantly substituted by fluorine,-   R2 is 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or    1-4C-alkoxy which is completely or predominantly substituted by    fluorine,-   R3 is 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or    1-4C-alkoxy which is completely or predominantly substituted by    fluorine,-   R4 is 1-4C-alkyl and-   R5 is hydrogen or 1-4C-alkyl,    -   or wherein-   R4 and R5 together and with inclusion of the two carbon atoms, to    which they are bonded, form a spiro-linked cyclopentane,    cyclohexane, tetrahydrofuran or tetrahydropyran ring,-   R6 and R7 represent independently from one another hydrogen or    1-4C-alkyl, or R6 and R7 together and with inclusion of the two    carbon atoms, to which they are bonded, form a group selected from:-   and A either represents —C_(m)H_(2m)—Y—X—C_(n)H_(2n)—, wherein    either    -   X represents a bond,    -   Y represents a bond,    -   m is an integer from 1 to 4, and    -   n is an integer from 1 to 4,    -   or    -   X represents a bond, —O—, —S—, —C(O)—, —S(O)₂—, —C(O)—NH— or        —C(S)—NH—,    -   Y represents 1,4-phenylene, 1,3-phenylene, 1,4-cyclohexylene,        1,3-cyclohexylene or 1,3-cyclopentylene,    -   m is an integer from 0 to 4, and    -   n is an integer from 1 to 4,    -   or    -   X represents a bond, —C(O)—, —S(O)₂—, —C(O)—NH— or —C(S)—NH—,    -   Y represents 4,1-piperidinylene,    -   m is 0, and    -   n is an integer from 1 to 4,    -   or    -   X represents a bond, —C(O)—, —S(O)₂—, —C(O)—NH— or —C(S)—NH—,    -   Y represents 1,4-piperazinylene,    -   m is an integer from 1 to 4, and    -   n is an integer from 1 to 4,-   or-   A represents —Y—X—C_(m)H_(2m)—Z—C_(n)H_(2n)—, wherein    -   X represents a bond, —C(O)—, —S(O)₂—, —C(O)—NH— or —C(S)—NH—,    -   Y represents 4,1-piperidinylene,    -   Z represents a bond, —O—, —S—, —S(O)₂— or —C(O)—NH—,    -   m is an integer from 1 to 4, and    -   n is an integer from 1 to 4,    -   or    -   X represents a bond, —O—, —S—, —C(O)—, —S(O)₂—, —C(O)—NH— or        —C(S)—NH—,    -   Y represents 1,4-phenylene, 1,3-phenylene, 1,4-cyclohexylene,        1,3-cyclohexylene or 1,3-cyclopentylene,    -   Z represents a bond, —O—, —S—, —S(O)₂— or —C(O)—NH—,    -   m is an integer from 1 to 4, and    -   n is an integer from 1 to 4,-   R8 is hydrogen, methyl or ethyl,-   Ar₂ represents a 8-hydroxy-1H-quinolin-2-on-5-yl radical or a phenyl    radical substituted by R9, R10 and R11, wherein-   R9 is hydrogen, halogen, hydroxyl, amino, ureido [—NH—C(O)—NH₂],    formylamino [—NH—C(O)H], 1-4C-alkylcarbonylamino,    di-1-4C-alkylaminocarbonyloxy, tolylcarbonyloxy [—O—C(O)—C₆H₄—CH₃],    hydroxymethyl, 1-4C-alkylcarbonyloxy, 1-4C-alkyl, 1-4C-alkoxy,    1-4C-alkylsulfonylamino, 1-4C-alkylsulfonylmethyl or    1-4C-alkoxy-1-4C-alkyl,-   R10 is hydrogen, halogen, hydroxyl, cyano, trifluoromethyl,    tolylcarbonyloxy [—O—C(O)—C₆H₄—CH₃], hydroxymethyl or    1-4C-alkylcarbonyloxy,-   R11 is hydrogen or halogen,    and the salts of these compounds.

Compounds of the formula I which are particularly to be emphasized arethose in which

-   Ar₁ represents a phenyl radical of formula (Ia) substituted by R1    and R2 or a dihydrobenzofuranyl radical of formula (Ib) substituted    by R3, R4 and R5:    wherein-   R1 is 1-2C-alkoxy or 1-2C-alkoxy which is completely or    predominantly substituted by fluorine,-   R2 is 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or    1-2C-alkoxy which is completely or predominantly substituted by    fluorine,-   R3 is 1-2C-alkoxy or 1-2C-alkoxy which is completely or    predominantly substituted by fluorine,-   R4 is methyl and-   R5 is hydrogen,    or wherein-   R4 and R5 together and with inclusion of the two carbon atoms, to    which they are bonded, form a spiro-linked cyclopentane or    cyclohexane ring,-   R6 and R7 together and with inclusion of the two carbon atoms, to    which they are bonded, form a group selected from:-   and A either represents —C_(m)H_(2m)—Y—X—C_(n)H_(2n)—, wherein    either    -   X represents a bond,    -   Y represents a bond,    -   m is an integer from 1 to 4, and    -   n is an integer from 1 to 4,    -   or    -   X represents a bond, —O— or —C(O)—NH—,    -   Y represents 1,4-phenylene or 1,4-cyclohexylene,    -   m is an integer from 0 to 4, and    -   n is an integer from 1 to 4,    -   or    -   X represents a bond, —C(O)—, —S(O)₂— or —C(S)—NH—,    -   Y represents 4,1-piperidinylene,    -   m is 0, and    -   n is an integer from 1 to 4,        or-   A represents —Y—X—C_(m)H_(2m)—Z—C_(n)H_(2n)—, wherein either    -   X represents a bond or —C(O)—,    -   Y represents 4,1-piperidinylene,    -   Z represents a bond, —S— or —S(O)₂—,    -   m is an integer from 1 to 4, and    -   n is an integer from 1 to 4,    -   or    -   X represents a bond, —O— or —C(O)—NH—,    -   Y represents 1,4-phenylene or 1,4-cyclohexylene,    -   Z represents a bond,    -   m is an integer from 1 to 4, and    -   n is an integer from 1 to 4,-   R8 is hydrogen,-   Ar₂ represents a 8-hydroxy-1H-quinolin-2-on-5-yl radical or a phenyl    radical substituted by R9, R10 and R11, wherein    -   R9 is hydrogen, hydroxyl or amino,    -   R10 is hydrogen, halogen, cyano, trifluoromethyl or        hydroxymethyl,    -   R11 is hydrogen or halogen,        and the salts of these compounds.

Preferred compounds of formula I are those in which

-   Ar₁ represents a phenyl radical of formula (Ia) substituted by R1    and R2 or a dihydrobenzofuranyl radical of formula (Ib) substituted    by R3, R4 and R5:    wherein-   R1 is methoxy or ethoxy,-   R2 is methoxy or ethoxy,-   R3 is methoxy,-   R4 and R5 together and with inclusion of the two carbon atoms, to    which they are bonded, form a spiro-linked cyclopentane ring,-   R6 and R7 together and with inclusion of the two carbon atoms, to    which they are bonded, form a group selected from:-   and A either represents —C_(m)H_(2m)—Y—X—C_(n)H_(2n)—, wherein    either    -   X represents a bond,    -   Y represents a bond,    -   m is an integer from 1 to 4, and    -   n is an integer from 1 to 4,    -   or    -   X represents a bond, —O— or —C(O)—NH—,    -   Y represents 1,4-phenylene,    -   m is an integer from 0 to 1, and    -   n is an integer from 1 to 4,    -   or    -   X represents a bond, —C(O)—, —S(O)₂— or —C(S)—NH—,    -   Y represents 4,1-piperidinylene,    -   m is 0, and    -   n is an integer from 1 to 4,        or-   A represents —Y—X—C_(m)H_(2m)—Z—C_(n)H₂—, wherein    -   X represents a bond or —C(O)—,    -   Y represents 4,1-piperidinylene,    -   Z represents a bond, —S— or —S(O)₂—,    -   m is 2 or 3, and    -   n is 2 or 3,-   R8 is hydrogen,-   Ar₂ is phenyl, 4-amino-3-chloro-5-cyanophenyl,    4-amino-3-chloro-5-trifluoromethylphenyl,    4-hydroxy-3-hydroxymethylphenyl, 4-amino-3-cyanophenyl or    4-amino-3,5-dichlorophenyl,    and the salts of these compounds.

One embodiment (embodiment A) of the compounds of formula I are those,in which

-   Ar₁ represents a phenyl radical of formula (Ia) substituted by R1    and R2 or a dihydrobenzofuranyl radical of formula (Ib) substituted    by R3, R4 and R5:    wherein-   R1 is hydroxyl, halogen, 1-4C-alkoxy or 1-4C-alkoxy which is    completely or predominantly substituted by fluorine,-   R2 is hydroxyl, halogen, 1-8C-alkoxy, 3-7C-cycloalkoxy,    3-7C-cycloalkylmethoxy, or 1-4C-alkoxy which is completely or    predominantly substituted by fluorine,-   R3 is 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or    1-4C-alkoxy which is completely or predominantly substituted by    fluorine,-   R4 is 1-4C-alkyl and-   R5 is hydrogen or 1-4C-alkyl,    or wherein-   R4 and R5 together and with inclusion of the two carbon atoms, to    which they are bonded, form a spiro-linked 5-, 6- or 7-membered    hydrocarbon ring, optionally interrupted by an oxygen or sulphur    atom,-   R6 and R7 represent independently from one another hydrogen or    1-4C-alkyl, or R6 and R7 together and with inclusion of the two    carbon atoms, to which they are bonded, form a group selected from:-   A represents —(CH₂)_(m)—Y—X—(CH₂)_(n)—, wherein    -   X represents a bond, —O— (oxygen), —S— (sulfur), —NH—, —C(O)—,        —C(O)—NH— or —NH—C(O)—NH—,    -   Y represents a bond, phenylene, 4-8C-cycloalkylene or        azacycloalkylene,    -   m is an integer from 0 to 4,    -   n is an integer from 1 to 4,-   R8 is hydrogen or 1-4C-alkyl,-   Ar₂ represents a 8-hydroxy-1H-quinolin-2-on-5-yl radical or a phenyl    radical substituted by R9, R10 and R11,    wherein-   R9 is hydrogen, halogen, hydroxyl, amino, ureido [—NH—C(O)—NH₂],    formylamino [—NH—C(O)H], 1-4C-alkylcarbonylamino,    di-1-4C-alkylaminocarbonyloxy, tolylcarbonyloxy [—O—C(O)—C₆H₄—CH₃],    hydroxymethyl, 1-4C-alkylcarbonyloxy, 1-4C-alkyl, 1-4C-alkoxy,    1-4C-alkylsulfonylamino, 1-4C-alkylsulfonylmethyl or    1-4C-alkoxy-1-4C-alkyl,-   R10 is hydrogen, halogen, hydroxyl, cyano, trifluoromethyl,    tolylcarbonyloxy [—O—C(O)—C₆H₄—CH₃], hydroxymethyl or    1-4C-alkylcarbonyloxy,-   R11 is hydrogen or halogen,    and the salts of these compounds.

Compounds of the formula I of embodiment A to be emphasized are those inwhich

-   Ar₁ represents a phenyl radical of formula (Ia) substituted by R1    and R2 or a dihydrobenzofuranyl radical of formula (Ib) substituted    by R3, R4 and R5:    wherein-   R1 is 1-4C-alkoxy or 1-4C-alkoxy which is completely or    predominantly substituted by fluorine,-   R2 is 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or    1-4C-alkoxy which is completely or predominantly substituted by    fluorine,-   R3 is 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or    1-4C-alkoxy which is completely or predominantly substituted by    fluorine,-   R4 is 1-4C-alkyl and-   R5 is hydrogen or 1-4C-alkyl,    -   or wherein-   R4 and R5 together and with inclusion of the two carbon atoms, to    which they are bonded, form a spiro-linked cyclopentane,    cyclohexane, tetrahydrofuran or tetrahydropyran ring,-   R6 and R7 represent independently from one another hydrogen or    1-4C-alkyl, or R6 and R7 together and with inclusion of the two    carbon atoms, to which they are bonded, form a group selected from:-   A represents —(CH₂)_(m)—Y—X—(CH₂)_(n)—, wherein    -   X represents a bond, —O— (oxygen), —NH—, —C(O)— or —C(O)—NH—,    -   Y represents a bond, phenylene, cyclopentylene, cyclohexylene,        piperidinylene or piperazinylene,    -   m is an integer from 0 to 4,    -   n is an integer from 1 to 4,-   R8 is hydrogen, methyl or ethyl,-   Ar₂ represents a 8-hydroxy-1H-quinolin-2-on-5-yl radical or a phenyl    radical substituted by R9, R10 and R11, wherein-   R9 is hydrogen, halogen, hydroxyl, amino, ureido [—NH—C(O)—NH₂],    formylamino [—NH—C(O)H], 1-4C-alkylcarbonylamino,    di-1-4C-alkylaminocarbonyloxy, tolylcarbonyloxy [—OC(O)—C₆H₄—CH₃],    hydroxymethyl, 1-4C-alkylcarbonyloxy, 1-4C-alkyl, 1-4C-alkoxy,    1-4C-alkylsulfonylamino, 1-4C-alkylsulfonylmethyl or    1-4C-alkoxy-1-4C-alkyl,-   R10 is hydrogen, halogen, hydroxyl, cyano, trifluoromethyl,    tolylcarbonyloxy [—O—C(O)—C₆H₄—CH₃], hydroxymethyl or    1-4C-alkylcarbonyloxy,-   R11 is hydrogen or halogen,    and the salts of these compounds.

Compounds of the formula I of embodiment A which are particularly to beemphasized are those in which

-   Ar₁ represents a phenyl radical of formula (Ia) substituted by R1    and R2 or a dihydrobenzofuranyl radical of formula (Ib) substituted    by R3, R4 and R5:    wherein-   R1 is 1-2C-alkoxy or 1-2C-alkoxy which is completely or    predominantly substituted by fluorine,-   R2 is 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or    1-2C-alkoxy which is completely or predominantly substituted by    fluorine,-   R3 is 1-2C-alkoxy or 1-2C-alkoxy which is completely or    predominantly substituted by fluorine,-   R4 is methyl and-   R5 is hydrogen,    or wherein-   R4 and R5 together and with inclusion of the two carbon atoms, to    which they are bonded, form a spiro-linked cyclopentane or    cyclohexane ring,-   R6 and R7 together and with inclusion of the two carbon atoms, to    which they are bonded, form a group selected from:-   A represents —(CH₂)_(m)—Y—X—(CH₂)_(n)—, wherein    -   X represents a bond or —C(O)—,    -   Y represents a bond, 1,4-phenylene, 1,4-cyclohexylene or        4,1-piperidinylene,    -   m is an integer from 0 to 4,    -   n is an integer from 1 to 4,-   R8 is hydrogen,-   Ar₂ represents a 8-hydroxy-1H-quinolin-2-on-5-yl radical or a phenyl    radical substituted by R9, R10 and R11, wherein-   R9 is hydrogen, hydroxyl or amino,-   R10 is hydrogen, halogen, cyano, trifluoromethyl or hydroxymethyl,-   R11 is hydrogen or halogen,    and the salts of these compounds.

Preferred compounds of formula I of embodiment A are those in which

-   Ar₁ represents a phenyl radical of formula (Ia) substituted by R1    and R2 or a dihydrobenzofuranyl radical of formula (Ib) substituted    by R3, R4 and R5:    wherein-   R1 is methoxy, ethoxy or difluoromethoxy,-   R2 is methoxy or ethoxy,-   R3 is methoxy,-   R4 and R5 together and with inclusion of the two carbon atoms, to    which they are bonded, form a spiro-linked cyclopentane ring,-   R6 and R7 together and with inclusion of the two carbon atoms, to    which they are bonded, form a group selected from:-   A represents —(CH₂)_(m)—Y—X—(CH₂)_(n)—, wherein    -   X represents a bond,    -   Y represents a bond or 1,4-phenylene,    -   m is an integer from 0 to 4,    -   n is an integer from 1 to 4,-   R8 is hydrogen,-   Ar₂ is phenyl, 4-amino-3-chloro-5-cyanophenyl,    4-amino-3-chloro-5-trifluoromethylphenyl,    4-hydroxy-3-hydroxymethylphenyl, 4-amino-3-cyanophenyl or    4-amino-3,5-dichlorphenyl,    and the salts of these compounds.

For the purpose of this invention the following numbering is used in thephthalazinone respectively pyridazinone part of the compounds of formulaI:Numbering Pyridazinone Compounds

Numbering Phthalazinone Compounds

The compounds of formula I are chiral compounds with—depending of themeaning of Ar₁—a chiral center in the dihydrobenzofuranyl radical, ifthe substituents —R4 and —CH₂R5 are not identical. However, preferredare those compounds, in which the substituents —R4 and —CH₂R5 areidentical or together and with inclusion of the carbon atoms to whichthey are bonded form a spiro-connected 5-, 6- or 7-membered hydrocarbonring.

Further possible chiral centers in the compounds of formula I are markedin the following formula I* with an asterix (*):

The invention includes all conceivable pure diastereomers and pureenantiomers, as well as all mixtures thereof independent from the ratio,including the racemates.

In those cases, wherein R6 and R7 together and with inclusion of the twocarbon atoms, to which they are bonded, form a group selected from:

those compounds are preferred, in which the hydrogen atoms in thepositions 4a and 8a are cis-configurated. Especially preferred in thisconnection are those compounds, in which the absolute configuration(according to the rules of Cahn, Ingold and Prelog) is S in the position4a and R in the position 8a.

(4a,8a)-cis-Racemates can be split up into the corresponding enantiomersby methods known by a person skilled in the art. Preferably the racemicmixtures are separated into two diastereomers during the preparationwith the help of an optical active separation agent on the stage of thecyclohexane-carboxylic acids or the 1,2,3,6-tetrahydrobenzoic acids. Asseparation agents may be mentioned, for example, optical active aminessuch as the (+)- and (−)-forms of 1-phenylethylamine[(R)-(+)-1-phenylethylamine=D-α-methylbenzylamine or(S)-(−)-1-phenylethylamine=L-α-methylbenzylamine) and ephedrine, theoptical active alkaloids quinine, cinchonine, cinchonidine and brucine.

The preparation of (4aS, 8aR) configurated4-(3,4-dialkoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-ones or4-(3,4-dialkoxyphenyl)-4a,5,6,7,8,8a-hexahydro-2H-phthalazin-1-ones isdescribed, for example, in the international application WO98/31674.

The preparation of (4aS, 8aR) configurated4-(2,3-dihydro-7-alkoxybenzofuran-2-spiro-1′-cyclopentan-4-yl)-4a,5,6,7,8,8a-hexahydro-2H-phthalazin-1-onesis described, for example, in the international application WO99/31090.

One group of preferred compounds of formula I are those in which thedivalent radical A has a longitudinal extension of about 4 to about 6carbon carbon bonds. Examples which may be mentioned in this connectionare tetramethylene, pentamethylene, hexamethylene or phenylethylene.

Another group of preferred compounds of formula I are those in which Yrepresents a 1,4-phenylene or 4,1-piperidinylene radical.

The invention further relates to processes for the preparation ofcompounds of formula I and their salts.

Several alternative synthetic routes to compounds of formula I aredescribed in the Reaction Schemes I to IX.

Reaction Scheme I describes the preparation of compounds of formula Istarting from 2H-phthalazin-1-one or 2H-pyridazin-1-one compounds. Theseare reacted in a first reaction with appropriate α,ω-dihalogenalkanes(if A represents an alkylene chain) to give the corresponding2-(ω-halogenalkyl)phthalazin-1-ones or 2-(ω-halogenalkyl)pyridazinones.In a second reaction these compounds are then converted to compounds offormula I through reaction with an 2-amino-1-(phenyl)ethanol derivative.Compounds of formula I in which A contains additional to the alkylenechain further groups, for example a 1,4-phenylene radical, can beprepared in an analogous manner.

Reaction Scheme II starts with the 2-(ω-halogenalkyl)phthalazin-1-onesor 2-(ω-halogenalkyl)pyridazinones already described in Reaction SchemeI. In a first reaction the halogen atom is replaced by an amino groupvia a Gabriel synthesis (for example as described in Angew. Chem. 80,986-996). The 1-(phenyl)ethanol part of the compounds of formula I isintroduced with the help of a 2-bromoacetophenone derivative followed bya reduction step.

Reaction Scheme III also starts with the2-(ω-halogenalkyl)phthalazin-1-ones or 2-(ω-halogenalkyl)pyridazinonesalready described in Reaction Scheme I. In this alternative the aminofunction is introduced through reaction with benzylamine. The1-(phenyl)ethanol part of the compounds of formula I is again introducedwith the help of a 2-bromoacetophenone derivative followed by areduction step. Finally the benzyl group is removed, for example, bycatalytic hydrogenation.

Further compounds of formula I, whose preparation is not explicitlydescribed in the above reaction schemes can be prepared analogously tothe methods described in the following examples or according tocustomary preparation methods known to the person skilled in the art.

All the starting compounds are known or can be prepared according tocustomary preparation methods known to the person skilled in the art.

The preparation of appropriate starting compounds with a phthalazinonestructure is described for example in WO98/31674, WO99/31090 orEP0934933. The preparation of appropriate starting compounds with apyridazinone structure is described for example in EPO163965.

Suitably, the conversions are carried out analogous to methods which arefamiliar per se to the person skilled in the art, for example, in themanner which is described in the following examples.

It is moreover known to the person skilled in the art that if there area number of reactive centers on a starting or intermediate compound itmay be necessary to block one or more reactive centers temporarily byprotective groups in order to allow a reaction to proceed specificallyat the desired reaction center. A detailed description for the use of alarge number of proven protective groups is found, for example, in T. W.Greene, Protective groups in organic Synthesis, John Wiley & Sons, 1991.

The substances according to the invention are isolated and purified in amanner known per se, e.g. by distilling off the solvent in vacuo andrecrystallizing the residue obtained from a suitable solvent orsubjecting it to one of the customary purification methods, such ascolumn chromatography on a suitable support material.

Salts are obtained by dissolving the free compound in a suitable solvent(for example a ketone like acetone, methylethylketone, ormethylisobutylketone, an ether, like diethyl ether, tetrahydrofuran ordioxane, a chlorinated hydrocarbon, such as methylene chloride orchloroform, or a low molecular weight aliphatic alcohol, such asethanol, isopropanol) which contains the desired acid or base, or towhich the desired acid or base is then added. The salts are obtained byfiltering, reprecipitating, precipitating with a non-solvent for theaddition salt or by evaporating the solvent. Salts obtained can beconverted by basification or by acidifying into the free compoundswhich, in turn, can be converted into salts. In this manner,pharmacologically non-tolerable salts can be converted intopharmacologically tolerable salts.

The following examples illustrate the invention in greater detail,without restricting it. The compounds, which are mentioned in theexamples as well as their salts are preferred compounds of theinvention.

EXAMPLES

Final Products

1.(cis)-2-(4-[{2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl}-amino]-1-butyl)-4-(3,4-dimethoxyphenyl)-4a,5,6,7,8,8a-hexahydro-2H-phthalazin-1-onefumarate

Prepared from compound 1a and compound A according to REACTION 2. M. p.85-88° C.

2.(cis)-2-(6-[{2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl}-amino]-1-hexyl)-4-(3,4-dimethoxyphenyl)-4a,5,6,7,8,8a-hexahydro-2H-phthalazin-1-onehemifumarate

Prepared from compound 1b and compound A according to REACTION 2. M. p.110-112° C.

3.(cis)-2-(8-[{2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl}-amino]-1-octyl)-4-(3,4-dimethoxyphenyl)-4a,5,6,7,8,8a-hexahydro-2H-phthalazin-1-onehemifumarate

Prepared from compound 1c and compound A according to REACTION 2. M. p.111-113° C.

4.(cis)-2-(6-[{2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl}-amino]-1-hexyl)-4-(3,4-diethoxyphenyl)-4a,5,6,7,8,8a-hexahydro-2H-phthalazin-1-onehemifumarate

Prepared from compound 1d and compound A according to REACTION 2. M. p.109-111° C.

5.(cis)-2-{4-(2-[{2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl}amino]-1-ethyl}phenyl)-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onehemifumarate

Prepared from compound 1j and compound A according to REACTION 2. M. p.121-125° C.

6.(cis)-2-(6-[{2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl}-amino]-1-hexyl)-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onehemifumarate

Prepared from compound 1e and compound A according to REACTION 2. M. p.119-122° C.

7.(cis)-2-(6-[{2-(4-amino-3,5,dichlorophenyl)-2-hydroxyethyl}amino]-1-hexyl)-4-(3,4-dimethoxyphenyl)-2H-phthalazin-1-onehemifumarate

Prepared from compound 1k and compound A according to REACTION 2. M. p.107-110° C.

8.(cis)-2-(2-[{2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl}amino]-1-ethyl)-4-(2,3-dihydro-7-methoxybenzofuran-2-spiro-1′-cyclopentan-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

Prepared from compound 1i and compound A according to REACTION 2. M. p.176-177° C.

9.(cis)-2-(4-[{2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl}amino]-1-butyl)-4-(2,3-dihydo-7-methoxybenzofuran-2-spiro-1′-cyclopentan-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onehemifumarate

Prepared from compound 1h and compound A according to REACTION 2. M. p.120-123° C.

10.(cis)-2-(6-[{2-(4-amino-3,5,dichlorophenyl)-2-hydroxyethyl}amino]-1-hexyl)-6-(3-methoxy-4-difluoromethoxyphenyl)-2H-pyridazin-3-onehemifumarate

Prepared from compound 1l and compound A according to REACTION 2. M. p.80-85° C.

11.(cis)-2-(4-[{2-(4-amino-3-chloro-5-cyanophenyl)-2-hydroxyethyl}amino]-1-butyl)-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onehemifumarate

Prepared from compound 3b and compound D according to REACTION 5. M. p.115-118° C.

12.(cis)-2-(5-[{2-(4-amino-3-chloro-5-cyanophenyl)-2-hydroxyethyl}amino]-1-pentyl)-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onehemifumarate

Prepared from compound 3c and compound D according to REACTION 5. M. p.121-123° C.

13.(cis)-2-(6-[{2-(4-amino-3-chloro-5-cyanophenyl)-2-hydroxyethyl}amino]-1-hexyl)-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onehemifumarate

Prepared from compound 3a and compound D according to REACTION 5. M. p.168-170° C.

14.(cis)-4-(3,4-dimethoxyphenyl)-2-(6-[{2-(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl}amino]-1-hexyl)-4a,5,6,7,8,8a-hexahydro-2H-phthalazin-1-onehemifumarate

Prepared from compound 1b and compound C according to REACTION 2. M. p.99-103° C.

15.(cis)-2-(8-[{2-(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl}amino]-1-octyl)-4-(3,4-dimethoxyphenyl)-5,6,7,8,9,10-hexahydro-1-phthalazinone3/4fumarate

Prepared from compound 1c and compound C according to REACTION 2. M. p.66-70° C.

16.(cis)-2-(6-[{2-(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl}amino]-1-hexyl)-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onehemifumarate

Prepared from compound 1e and compound C according to REACTION 2. M. p.96-99° C.

17.(cis)-2-(6-[{2-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-hydroxyethyl}amino]-1-hexyl)-4-(3,4-dimethoxyphenyl)-4a,5,6,7,8,8a-hexahydro-2H-phthalazin-1-one3/4fumarate

Prepared from compound 1b and compound B according to REACTION 2. M. p.102-105° C.

18.(cis)-2-(6-[{2-(4-amino-3-cyanophenyl)-2-hydroxyethyl}amino]-1-hexyl)-4-(3,4-dimethoxyphenyl)-4a,5,6,7,8,8a-hexahydro-2H-phthalazin-1-onehemifumarate

Prepared from compound 4 and compound E according to REACTIONS 7, 8 and9. M. p. 101-103° C.

19.(cis)-4-(3,4-dimethoxyphenyl)-2-[6-{(2-phenyl-2-hydroxyethyl)amino}-1-hexyl]4a,5,6,7,8,8a-hexahydro-2H-phthalazin-1-one3/4fumarate

Prepared from compound 1b and 2-amino-1-phenylethanol according toREACTION 2. M. p. 110-115° C.

20.2-Amino-3-chloro-5-[2-(4-{4-[(4aS,8aR)-4-(3,4-dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-4-oxo-butylamino)-1-hydroxy-ethyl]-benzonitrilefumarate

Prepared from starting compound 5a and starting compound D according toREACTION 5. M. p. 212-216° C.

21.(4aS,8aR)-2-(4-{4-[2-(4-Amino-3,5-dichlorophenyl)-2-hydroxy-ethylamino]-butoxyl}-phenyl)-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onefumarate

Prepared from compound 6a and compound A according to REACTION 2. M. p.126-127° C.

22.(4aS,8aR)-2-(4-{4-[2-(4-Amino-3,5-dichloro-phenyl)-2-hydroxy-ethylamino]-butoxy}-benzyl)-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onefumarate

Prepared from compound 7a and compound A according to REACTION 2. M. p.119-120° C.

23.(4aS,8aR)-2-(4-{2-[2-(4-Amino-3,5-dichloro-phenyl)-2-hydroxy-ethylamino]-ethoxy}-phenyl)-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-oneoxalate

Prepared from compound 8a and compound A according to REACTION 2. M. p.136-138° C.

24.(4aS,8aR)-2-[1-(2-{2-[2-(4-Amino-3,5-dichloro-phenyl)-2-hydroxy-ethylamino]-ethanesulfonyl}-ethyl)-piperidin-4-yl]-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onefumarate

Prepared from compound 9a and compound A according to REACTION 10. M. p.137-138° C.

25.4-[(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carbothioicacid{4-[2-(4-amino-3,5-dichloro-phenyl)-2-hydroxy-ethylamino]-butyl}-amide

Prepared from compound 10a and compound O according to REACTION 5. M. p.139-144° C.

26.(4aS,8aR)-2-(1-{2-[2-(4-Amino-3,5-dichloro-phenyl)-2-hydroxy-ethylamino]-ethanoyl}-piperidin-4-yl)-4-(3,4-diethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onefumarate

Prepared from compound 11a and compound A according to REACTION 2. M. p.172-173° C.

27.(4aS,8aR)-2-(1-{2-[2-(4-Amino-3,5-dichloro-phenyl)-2-hydroxy-ethylamino]-ethanesulfonyl}-piperidin-4yl)-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onefumarate

Prepared from compound 12a and compound A according to REACTION 2. M. p.169-171° C.

28.(4aS,8aR)-2-(1-{(S)-2-[2-(3,4-Diamino-5-chloro-phenyl)-2-hydroxy-ethylamino]-propanoyl}-piperidin-4-yl)-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onefumarate

Prepared from compound 13a and compound O according to REACTION 5. M. p.130-131° C.

29.(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-(1-{2-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-ethanesulfonyl}-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

Prepared from compound 12a and compound C according to REACTION 10.Crystallised as the free base from ethyl acetate. M. p. 97-99° C.

30.(4aS,8aR)-2-[1-(3-{2-[2-(4-Amino-3,5-dichloro-phenyl)-2-hydroxy-ethylamino]-ethylsulfanyl}-propanoyl)-piperidin-4-yl]-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onehydrochloride

Prepared from compound O and compound 14a according to REACTION 5. M. p.118-120° C.

31.(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-(4-{4-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-butoxy}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onefumarate

Prepared from compound 6a and compound C according to REACTION 2. M. p.126-127° C.

32.2-Amino-3-chloro-5-{2-[2-(3-{4-[(4aS,8aR)-4-(3,4-dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-3-oxo-propane-1-sulfonyl)-ethylamino]-1-hydroxy-ethyl}-benzonitrile

Prepared from compound 15a and compound D according to REACTION 5.Crystallised from diethyl ether as the free base. M. p. 102-103° C.

33.2-Amino-3-chloro-5-[2-((S)-2-{4-[(4aS,8aR)-4-(3,4-dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-1-methyl-2-oxo-ethylamino)-1-hydroxy-ethyl]-benzonitrilehydrochloride

Prepared from compound 13a and compound D according to REACTION 5.Crystallised as the hydro-chloride. M. p. 160-161° C.

34.2-Amino-3-chloro-5-[2-(6-{4-[(4aS,8aR)-4-(3,4-dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-hexylamino)-1-hydroxy-ethyl]-benzonitrilefumarate

Prepared from compound 16a and compound D according to REACTION 5. M. p.142-143° C.

General Synthesis Reaction 1 2-(ω-halogenalkyl)phthalazinones (compounds1a-1h, 1k or 1l)

25 mmol of sodium hydride is added to a stirred solution of 20 mmol of aphthalazinone or a pyridazinone (compounds F-K) in 50 ml ofdimethylformamide. After 5 min, 60 mmol of a α,ω-dihalogenalkane isadded and the resulting mixture stirred for 60 min. After the additionof 200 ml of water, the mixture is extracted with diethyl ether. Theether solution is dried over magnesium sulfate and evaporated. Theresidue is purified by chromatography [ethyl acetate:petroleum ether(60-80° C.)/1:4].

Reaction 2 Aminoethanol Derivatives

A mixture of 8 mmol of a 2-(ω-halogenalkyl)phthalazinone, 10 mmol of aprimary aminoethanol derivative (compounds A, B or C) and 20 mmol ofpotassium carbonate in 50 ml of dimethylformamide is heated for 1.5 h at100° C. After cooling to room temperature, a mixture of 100 ml of waterand 200 ml of ethyl acetate is added. The organic layer is dried overmagnesium sulfate and evaporated. The residue is purified bychromatography (ethyl acetate:triethyl amine/20:1). The aminoethanolderivative is crystallized as a salt with fumaric acid fromtetrahydrofurane/diethyl ether.

Reaction 3 Phthalimides (Compounds 2a, 2b or 2c)

15 mmol of a 2-(ω-halogenalkyl)phthalazinone, 18 mmol of phthalimide and20 mmol of potassium carbonate in 100 ml of dimethylformamide is heatedfor 5 h at 110° C. After cooling to room temperature, 300 ml of waterand 300 ml of ethyl acetate is added. The organic layer is dried overmagnesium sulfate and concentrated under reduced pressure. The compoundis crystallized from a suitable solvent.

Reaction 4 2-((ω-aminoalkyl)phthalazinone (compounds 3a, 3b or 3c)

A solution of 20 mmol of a phthalimide (compounds 2a, 2b or 2c) and 25mmol of hydrazine hydrate in 200 ml of ethanol is refluxed for 5 h andsubsequently evaporated. The residue is dissolved in ethyl acetate (200ml) and this solution is washed with aqueous sodium carbonate. Afterdrying over magnesium sulfate, the solvent is evaporated and the residuecrystallized from a suitable solvent.

Reaction 5 Aminoethanol Derivatives

A solution of 6 mmol of a 2-bromoacetophenone derivative (for example:compounds D or E), 5 mmol of an amine (for example: compounds 3a, 3b or3c) and 10 mmol of diisopropylethylamine in a mixture of 50 ml oftetrahydrofurane and 50 ml of methanol is stirred at room temperature.After 3 h 10 mmol of sodium borohydride is added and the resultingmixture is stirred for another hour and than evaporated. The residue isdissolved in water (100 ml) and this mixture is extracted twice with 200ml of ethyl acetate. The organic solution is dried over magnesiumsulfate and evaporated. The residue is purified by chromatography (ethylacetate:methanol:triethyl amine/10:2:0.5). The compound is crystallizedas a fumarate salt from tetrahydrofurane/diethyl ether.

Reaction 6 Benzylamines

A mixture of 25 mmol of a 2-(ω-halogenalkyl)phthalazinone and 200 mmolof benzylamine is heated at 120° C. for 2 h. After cooling to about 60°C., 200 ml of 2 N hydrobromic acid is added and the resulting mixtureis, after cooling to room temperature, extracted twice with 200 ml ofdichloromethane. The organic solution is dried over magnesium sulfateand evaporated. The residue is washed with diethyl ether and dried.

Reactions 7/8/9

A solution of 10 mmol of a benzylamine (compounds prepared according toREACTION 6), 10 mmol of a 2 bromoacetophenone derivative and 20 mmol ofdiisopropylethylamine in a mixture of 50 ml of tetrahydrofurane and 50ml of ethanol is stirred for 18 h at room temperature after which 10mmol of sodium borohydride is added. This mixture is stirred for another30 min and subsequently evaporated. The residue is dissolved in 200 mlof diethyl ether and this solution is washed with aqueous sodiumcarbonate. The organic solution is dried over magnesium sulfate andevaporated. The residue is dissolved in ethanol and, after the additionof 0.5 g of 5% Pd/C, treated with a flow of hydrogen. After about 60 mindebenzylation is completed (tlc analysis). The catalyst is filtered off,the solvent is evaporated and the residue purified by chromatography onsilica (ethyl acetate:triethyl amine/20:1). The aminoethanol derivativeis crystallized as a fumarate salt from tetrahydrofurane/diethyl ether.

Reaction 10

A mixture of 5 mmol of an ethenesulfonyl derivative (compounds 9a or12a) and 5 mmol of an aminoethanol derivative (compounds A, B or C) in50 ml of tetrahydrofuran is stirred for 18 h at RT, after which thesolvent is evaporated and the residue purified by chromatography(elution with ethyl acetate containing 5% of triethylamine).

Starting Compounds and Intermediates

1a:(cis)-2-(4-bromo-1-butyl)-4-(3,4-dimethoxyphenyl)-4a,5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Prepared from compound F and 1,4-dibromobutane according to REACTION 1.M. p. oil

1H-NMR(CDCl₃): 1.28-2.00 (m, 11H, 7xcyclohexane-H, C—(CH₂)₂—C);2.50-2.61 (m, 1H, cyclohexane-H); 2.63-2.73 (m, 1H, cyclohexane-H);3.00-3.15 (m, 1H, cyclohexane-H); 3.49 (t, J=6.4 Hz, 2H, CH₂—Br);3.72-4.12 (m, 8H, 2×O—CH₃, N—CH₂); 6.87 (d, J=8.4 Hz, 1H, Ar—H); 7.23(dd, J=2.1, 8.5 Hz, 1H, Ar—H); 7.47 (d, J=2.0 Hz, 1H, Ar—H).

1b:(cis)-2-(6-bromo-1-hexyl)-4-(3,4-dimethoxyphenyl)-4a,5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Prepared from compound F and 1,6-dibromohexane according to REACTION 1.Crystallized from diethyl ether. M. p. 74-75° C.

1c:(cis)-2-(8-bromo-1-octyl)-4-(3,4-dimethoxyphenyl)-4a,5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Prepared from compound F and 1,8-dibromooctane according to REACTION 1.Crystallized from hexane. M. p. 58-60° C.

1d:(cis)-2-(6-bromo-1-hexyl)-4-(3,4-diethoxyphenyl)-4a,5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Prepared from compound H and 1,6-dibromohexane according to REACTION 1.M. p. 47-51° C.

1e:(cis)-2-(6-bromo-1-hexyl)-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

Prepared from compound G and 1,6-dibromohexane according to REACTION 1.Crystallized from methanol. M. p. 55-56° C.

1H-NMR(CDCl₃): 1.37-2.26 (m, 11H, 3xcyclohexene-H, C—(CH₂)₄—C);2.67-2.81 (m, 1H, cyclohexene-H); 2.97-3.07 (m, 1H, cyclohexane-H);3.28-3.42 (m, 3H, CH₂—Br, cyclohexene-H); 3.68-4.06 (m, 8H, 2×O—CH₃,N—CH₂); 6.88 (d, J=8.5 Hz, 1H, Ar—H); 7.26 (dd, J=2.1, 8.5 Hz, 1H,Ar—H); 7.48 (d, J=2.0 Hz, 1H, Ar—H).

1f:(cis)-2-(4-bromo-1-butyl)-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

Prepared from compound G and 1,4-dibromobutane according to REACTION 1.Crystallized from methanol. M. p. 102-103° C.

1g:(cis)-2-(5-bromo-1-pentyl)-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

Prepared from compound G and 1,5-dibromopentane according to REACTION 1.M. p. oil.

1H-NMR(CDCl₃): 1.38-2.28 (m, 11H, 3xcyclohexene-H, C—(CH₂)₃—C);2.67-2.81 (m, 1H, cyclohexene-H); 2.97-3.07 (m, 1H,cyclohexene-H);3.28-3.50 (m, 3H, CH₂—Br, cyclohexene-H); 3.68-4.08 (m, 9H, 2×O—CH₃,N—CH₂, cyclohexene-H); 5.60-5.87 (m, 2H, CH═CH); 6.88 (d, J=8.5 Hz, 1H,Ar—H); 7.26 (dd, J=2.0, 8.5 Hz, H, Ar—H); 7.48 (d, J=2.0 Hz, 1H, Ar—H).

1h:(cis)-2-(4-bromo-1-butyl)-4-(2,3-dihydro-7-methoxybenzofuran-2-spiro-1′-cyclopentan-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

Prepared from compound I and 1,4-dibromobutane according to REACTION 1.Crystallized from methanol. M. p. 86-88° C.

1i:(cis)-2-bromoethyl-4-(2,3-dihydro-7-methoxybenzofuran-2-spiro-1′-cyclopentan-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

A solution 1.92 g of Br₂ in CH₂Cl₂ is added to a solution of 3.1 g oftriphenylphosphine in CH₂Cl₂ at 0° C. followed by the addition of asolution of 4.6 g of compound L in CH₂Cl₂. The resulting solution isstirred for 2 h at room temperature and subsequently washed with dilutedhydrochloric acid (2×) and aqueous sodium carbonate. Crystallizationfrom methanol (2×). M. p. 143-145° C.

1j:(cis)-2-{4-(2-bromoethyl)phenyl}-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

Prepared from M as described for intermediate 1i. Crystallized frommethanol. M. p. 126-127° C.

1k: 2-(6-bromo-1-hexyl)-4-(3,4-dimethoxyphenyl)-2H-phthalazin-1-one

Prepared from compound J and 1,6-dibromohexane according to REACTION 1.Crystallized from a mixture of ethyl acetate and hexane. M. p. 83-84° C.

1l:2-(6-bromo-1-hexyl)-4-(3-methoxy-4-difluoromethoxyphenyl)-2H-pyridazin-1-one

Prepared from compound K and 1,6-dibromohexane according to REACTION 1.Crystallized from diethyl ether. M. p. 69-70° C.

2a:(cis)-N-[6-{4-(3,4-dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-2H-phthalazin-2-yl}hexyl]-phthalimide

Prepared from compound 1e according to REACTION 3. Crystallized frommethanol. M. p. 104-105° C.

2b:(cis)-N-[4-{4-(3,4-dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-2H-phthalazin-2-yl}butyl]-phthalimide

Prepared from compound 1f according to REACTION 3. Crystallized frommethanol. M. p. 139-140° C.

2c:(cis)-N-[5-{4-(3,4-dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-2H-phthalazin-2-yl}pentyl]-phthalimide

Prepared from compound 1g according to REACTION 3. Crystallized fromdiethyl ether. M. p. 126-129° C.

3a:(cis)-2-(6-amino-1-hexyl)-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

Prepared from compound 2a according to REACTION 4. Crystallized fromtetrahydrofurane/diethyl ether as a fumarate salt. M. p. 141-143° C.

3b:(cis)-2-(4-amino-1-butyl)-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

Prepared from compound 2b according to REACTION 4. Crystallized fromdiethyl ether. M. p. 108-109° C.

3c:(cis)-2-(5-amino-1-pentyl)-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

Prepared from compound 2c according to REACTION 4. Crystallized fromdiethyl ether. M. p. 88-89.

4a:(cis)-2-(6-benzylamino-1-hexyl)-4-(3,4-dimethoxyphenyl)-4a,5,6,7,8,8a-hexahydro-2H-phthalazin-1-oneHBr

Prepared from compound 1b according to REACTION 6. M. p. 117-119° C.

5a:(4aS,8aR)-2-[1-(4-amino-butanoyl)-piperidin-4-yl]-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onetrifluoroacetate

15 mmol of compound 5b is dissolved in 20 ml of trifluoroacetic acid andthe solution is left at RT for 30 min after which it is evaporated. Theresidue solidifies on treating with diethyl ether. M. p. 175-178° C.

5b:(4-{4-[(4aS,8aR)-4-(3,4-dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro1H-phthalazin-2-yl]-piperidin-1-yl}-4-oxo-butyl)-carbamicacid tert butyl ester

To a solution of 20 mmol of compound 5c and 25 mmol of(4-Oxo-pentyl)-carbamic acid tert-butyl ester in 100 ml ofdichloromethane, 25 mmol of (3-dimethylamino-propyl)-ethyl-carbodiimidehydrochloride is added and the resulting mixture is stirred at RT. After18 h the solution is washed successively with diluted hydrochloric acidand aqueous sodium carbonate and then dried over magnesium sulfate.After evaporating the solvent, the compound is crystallised from hexane.M. p. 79-83° C.

5c:(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-piperidin-4-yl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

A solution of 50 mmol of compound 5d in 150 ml of dichloromethane iswashed with a saturated solution of sodium bicarbonate, dried overmagnesium sulfate and evaporated. The residue is washed with diethylether and dried. M. p. 260° C. (with decomposition).

5d:(4aS,8aR)-4-(3,4-Dimethoxy-phonyl)-2-piperidin-4-yl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onehydrochloride

A solution of 50 mmol of the salt of (S)-(−)-α-methylbenzylamine and(cis)-2-(3,4-dimethoxybenzoyl)-1,2,3,6-tetrahydrobenzoic acid (compoundN), 55 mmol of piperidin-4-yl-hydrazine dihydrochloride and 100 mmol oftriethylamine in 150 ml of 1-propanol is refluxed for 18 h. Aftercooling to RT, the precipitate is filtered off and dried. M. p. 285-288°C.

5e: Piperidin-4-yl-hydrazine dihydrochloride

A mixture of 0.1 mole of4-(N′-tert-butoxycarbonyl-hydrazino)-piperidine-1-carboxylic acidtert-butyl ester (compound 5f) and 150 ml of concentrated hydrochloricacid is heated at 90° C. for 60 min after which the clear solution isevaporated. The residue is washed with tetrahydrofurane, filtered offand dried under vacuum. M. p. 256-259° C.

5f: 4-(N′-tert-Butoxycarbonyl-hydrazino)-piperidine-1-carboxylic acidtert-butyl ester

150 ml of a solution of borohydride in tertahydrofurane (1.0 mol/l) isslowly added to a solution of 0.12 mole of4-(tert-butoxycarbonyl-hydrazono)-piperidine-1-carboxylic acidtert-butyl ester (compound 5 g) in 100 ml of dry tetrahydrofurane. Aftercomplete addition, the mixture is stirred for another 30 min after whicha 100 ml of water is added to destroy the excess of borohydride.Subsequently the tetrahydrofurane is evaporated and the resulting aqeoussolution extracted with diethyl ether. After drying the solvent overmagnesium sulfate, the ether is evaporated. M. p. 112-115° C.

5g: 4-(tert-Butoxycarbonyl-hydrazono)-piperidine-1-carboxylic acidtert-butyl ester

A mixture of 0.15 mole of 4-oxo-piperidine-1-carboxylic acid tert-butylester (commercially available) and 0.15 mole of tert-butylcarbazate in250 ml of hexane is stirred for 18 h at RT. The precipitate is filteredoff and dried under vacuum. M. p. 172-174° C.

6a:(4aS,8aR)-2-[4-(4-Bromo-butoxy)-phenyl]-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

A mixture of 10 mmol of compound 6b, 50 mmol of 1,4-dibromobutane and 40mmol of potassium carbonate in 50 ml of dimethylformamide is stirred for18 h at RT, after which the mixture is poured into 200 ml of water.After extraction with diethyl ether, the compound is purified bychromatography (ethyl acetate:hexane/1;5). Crystallised from hexane at−20° C. M. p. 38-43° C.

6b:(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-(4-hydroxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

A mixture of 20 mmol of compound 6c, 50 ml of ethanethiol and 20 ml ofborontrifluoride etherate is left at RT for 40 h. After the addition of200 ml of a saturated solution of sodium bicarbonate, the mixture isextracted with ethyl acetate. The organic solution is dried overmagnesium sulfate and evaporated. The compound is crystallised fromdiethyl ether. M. p. 111-112° C.

6c:(4aS,8aR)-2-(4Benzyloxy-phenyl)-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

A solution of 50 mmol of compound 6d and 50 mmol of4-benzyloxyphenylhydrazine hydrochloride in 100 ml of pyridine isrefluxed for 8 h and subsequently evaporated. The residue is dissolvedin ethyl acetate and the solution is washed successively with dilutedhydrochloric acid and aqueous sodium carbonate and then dried overmagnesium sulfate. After evaporating the solvent, the compound iscrystallised from methanol. M. p. 104-105° C.

6d:(1R,6S)-6-[1-(3,4-dimethoxy-phenyl)-methanoyl]-1,2,3,6-tetrahydrobenzoicacid

A solution of 50 mmol of compound 6e in 150 ml of dichloromethane iswashed successively with 1 N sulfuric acid and water (twice). Thesolution is dried over magnesium sulfate and evaporated. The residue iscrystallised from diethyl ether. M. p. 110-112° C.

6e:(1R,2S)-2-(3,4-Dimethoxy-phenyl)-methanoyl)-1,2,3,6-tetrahydrobenzoicacid (−)-α-methylbenzylamine salt

A mixture of 10 mmol of compound N and 5 mmol of L-α-methylbenzylaminein 100 ml of ethyl acetate is stirred for 18 h after which theprecipitate is filtered off and dried.

7a:(4aS,8aR)-2-[4-(4-Bromo-butoxy)-benzyl]-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

Prepared from compound 7b and 1,4-dibromobutane as described forcompound 6a. M. p. 42-46° C.

7b:(4aS,8aR)-4-(3,4-Dimethoxy-phonyl)-2-(4-hydroxy-benzyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

Prepared from 4-hydroxybenzylhydrazine hydrochloride and compound 6d asdescribed for compound 6c. Crystallised from diethyl ether. M. p.189-190° C.

8a:(4aS,8aR)-2-[4-(2-Bromo-ethoxy)-phenyl]-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

Prepared from compound 6b and 1,2-dibromoethane as described forcompound 6a. M. p. 40-45° C.

9a:(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-[1-(2-ethenesulfonyl-ethyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

A solution of 10 mmol of compound 5c, 10 mmol of1-bromo-2-(2-bromo-ethanesulfonyl)-ethane and 30 mmol of potassiumcarbonate in 30 ml of dimethylformamide is stirred at RT. After 18 h,the mixture is poured into water (150 ml) and subsequently extractedwith ethyl acetate. Crystallisation from diethyl ether. M. p. 165-166°C.

10a:4-[(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carbothioicacid (4-amino-butyl)-amide trifluoroacetate

Prepared from compound 10b as described for compound 5a. M. p. 125-128°C.

10b:{4-[(1-{4-[(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1-phthalazin-2-yl]-piperidin-1-yl}-methanethioyl)-amino]-butyl}-carbamicacid tert butyl ester

A solution of 10 mmol of (4-Isothiocyanato-butyl)-carbamic acid tertbutyl ester and 10 mmol of compound 5c in 100 ml of dichloromethane isstirred for 18 h at RT, successively washed with diluted hydrochloricacid and aqueous sodium carbonate and subsequently dried over magnesiumsulfate and evaporated. Crystallised from a mixture of ethyl acetate andhexane. M. p. 118-121° C.

11a:(4aS,8aR)-2-[1-(2-Chloro-ethanoyl)-piperidin-4-yl]-4-(3,4-diethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

A solution of 12 mmol of chloroacetylchloride in 20 ml ofdichloromethane is added at 0° C. to a mixture of 12 mmol of compound11b and 40 mmol of triethylamine in 50 ml of dichloromethane. Theresulting mixture is stirred for 60 min at RT and subsequently washedwith diluted hydrochloric acid and aqueous sodium carbonate. Afterdrying the solution over magnesium sulfate, the solvent is evaporatedand the residue purified by chromatography (ethyl acetate:petroleumether (60-80° C.)/2:1). M. p. 135-136° C.

11b:(4aS,8aR)-4-(3,4-Diethoxy-phenyl)-2-piperidin-4-yl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onehydrochloride

Prepared from the salt of (S)-(−)-α-methylbenzylamine,(cis)-2-(3,4-diethoxybenzoyl)-1,2,3,6-tetrahydrobenzoic acid (compoundP) and piperidin-4-yl-hydrazine dihydrochloride in 2-propanol asdescribed for compound 5d. M. p. 248-250° C.

12a:(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-(1-ethenesulfonyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

A solution of 20 mmol of 2-chloroethylsulfonylchloride in 20 ml ofdichloromethane is added to a solution of 15 mmol of compound 5c and 25ml of diisopropylethylamine in 50 ml of dichloromethane. The resultingmixture is stirred at RT for 18 h, after which it is washed first withdiluted hydrochloric acid and then with a saturated solution of sodiumbicarbonate. After drying over magnesium sulfate and evaporating thesolvent, the compound is crystallised from diethyl ether. M. p. 89-90°C.

13a:(4aS,8aR)-2-[1-((S)-2-Amino-propanoyl)-piperidin-4-yl]-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

Prepared from compound 13b as described for compound 5a. Afterevaporating the trifluoroacetic acid, the residue is partitioned betweenaqueous sodium carbonate and dichloromethane. The organic solution isdried over magnesium sulfate and evaporated. The residue is crystallisedfrom diethyl ether. M. p. 101-103° C.

13b:1-tert-Butyl-3-((S)-2-{4-[(4aS,8aR)-4-(3,4-dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-1-methyl-2-oxo-ethyl)-urea

Prepared from compound 5c and (R)-2-(3-tert-butyl-ureido)-propionic acid(N-boc-L-alanine) as described for compound 5b. M. p. 153-154° C.

14a.(4aS,8aR)-2-{1-[3-(2-Amino-ethylsulfanyl)-propanoyl]-piperidin-4-yl}-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

Prepared from compound 14b as described for compound 5c. Afterevaporating the trifluoroacetic acid, the residue is partitioned betweena bicarbonate solution and dichloromethane. The dichloromethane solutionis dried over magnesium sulfate and evaporated. Crystallised from ethylacetate/hexane. M. p. 137-139° C.

14b.[2-(3-{4-[(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-3-oxo-propylsulfanyl)-etyl]-carbamicacid tert butyl ester

Prepared from 12 mmol of3-(2-tert-butoxycarbonylamino-ethylsulfanyl)-propionic acid and 10 mmolof compound 5c as described for compound 5b. M. p. 132-134° C.

15a.(4aS,8aR)-2-{1-[3-(2-Amino-ethanesulfonyl)-propanoyl]-piperidin-4-yl}-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onehydrochloride

20 mmol of 3-chloroperbenzoic acid is added to a solution of 10 mmol ofcompound 14a in 50 ml of dichioromethane. The resulting mixture isstirred for 30 min at RT and subsequently washed with aqueous sodiumcarbonate. After drying over magnesium sulfate, a solution ofhydrochloric acid in diethyl ether is added to the dichloromethanesolution. The precipitate is filtered off and dried. M. p. 149-150° C.

16a.(4aS,8aR)-2-[1-(6-Amino-hexyl)-piperidin-4-yl]-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onehydrochloride

Prepared from compound 16b as described in REACTION 4. Crystallised fromethyl acetate as the hydrochloride. M. p. 176-177° C.

16b.2-(6-{4-[(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-hexyl)-isoindole-1,3-dione

A mixture of 6 mmol of 2-(6-bromo-hexyl)-isoindole-1,3-dione, 6 mmol ofcompound 5c and 3 g of potassium carbonate in 50 ml of dimethylformamideis stirred for 18 h at RT. After evaporating the solvent, the residue ispartitioned between water and ethyl acetate. The organic layer is driedover magnesium sulfate and evaporated. The residue is purified bychromatography (ethyl acetate:hexane/4:1). M. p. 39-44° C.

A: 2-amino-1-(4-amino-3,5-dichlorophenyl)ethanol

Prepared as described in J. Keck, G. Kruger, K. Noll and H. Machleidt;Arzneim.-Forsch. (Drug Res.) 22, 861-869 (1972).

B: 2-amino-1-(4-amino-3-chloro-5-trifluoromethylphenyl)ethanol

Prepared as described in G. Krülger, J. Keck, K. Noll and H. Pieper;Arzneim.-Forsch./Drug Res. 34, 1612-1624 (1984).

C: 2-amino-1-(4-hydroxy-3-hydroxymethylphenyl)ethanol

Prepared as described in D. T. Cullin, D. Hartley, L. H. C. Lunts, J. C.Press, A. C. Ritchie and P. Toon; J. Med. Chem., 13, 674-680 (1970).

D: 4′-amino-3′-chloro-5′-cyano-2-bromoacetophenone

Prepared as described in G. Krüger, J. Keck, K. Noll and H. Pieper;Arzneim.-Forsch./Drug Res. 34, 1612-1624 (1984).

E: 4′-amino-3′-cyano-2-bromoacetophenone

Prepared as described in G. Krüger, J. Keck, K. Noll and H. Pieper;Arzneim.-Forsch./Drug Res. 34, 1612-1624 (1984).

F: 4-(3,4-dimethoxyphenyl)-4a,5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Prepared as described in example 1 of WO98/31674.

G: 4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

Prepared as described in example 3 of WO98/31674.

H: 4-(3,4-diethoxyphenyl)-4a,5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

Prepared as described in example 7 of WO98/31674.

I:(cis)-4-(2,3-dihydro-7-methoxybenzofuran-2-spiro-1′-cyclopentan-4-yl)-4a,5,8,8a-tetra-hydro-2H-phthalazin-1-one

Prepared as described in example 4 of WO99/31090.

J: 4-(3,4-dimethoxyphenyl)-2H-phthalazin-1-one

Prepared as described in example B of EP0934933.

K: 4-(4-Difluoromethoxy-3-methoxyphenyl)-2H-pyridazin-1-one

Prepared as described in example 4 of EP0163965.

L:(cis)-4-(2,3-dihydro-7-methoxybenzofuran-2-spiro-1′-cyclopentan-4-yl)-2-hydroxyethyl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

Prepared as described in example 17 of WO99/31090.

M:(cis)-4-(3,4-dimethoxyphenyl)-2-{4-(2-hydroxyethyl)phonyl}-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

Prepared as described in example 70 of WO98/31674.

N. (cis)-2-(3,4-Dimethoxybenzoyl)-1,2,3,6-tetrahydrobenzoic acid

Prepared as described in WO98/31674.

O. 1-(4-Amino-3,5-dichloro-phenyl)-2-bromo-ethanone

Prepared as described by J. Keck, G. Krüger, K. Noll and H. Machleidt;Arzneim.-Forsch. (Drug Res.) 22, 861-869 (1972).

P. (cis)-2-(3,4-diethoxybenzoyl)-1,2,3,6-tetrahydrobenzoic acid

Prepared analogously as described for compound N.

Commercial Applicability

β-Sympathomimetics (β2-adrenoreceptor agonists) represent the preferreddrugs for the acute relief of bronchospasm in patients with bronchialasthma (Nelson H S, β-Adrenergic bronchodilators. The New England ofMedicine 333: 499-506, 1995). Although the major action ofβ-sympathomimetics on the airways is relaxation of airway smooth muscle,inhibitory effects on inflammatory cells (e.g. mast cells, eosinophils,neutrophils, macrophages and T-lymphocytes) in vitro have been reported(Barnes P J, Effect of beta-agonists on inflammatory cells. Journal ofAllergy and Clinical Immunology 104: S10-S17, 1999). Despite theinhibitory effects on inflammatory cells in vitro, however,β-sympathomimetics do not appear to reduce the chronic inflammation ofasthma. Desensitization to the action of β-sympathomimetics is morereadily seen in inflammatory cells than in airway smooth muscle cellsand may account for this discrepancy. It has been suggested that anaccelerated degradation of cAMP by phosphodiesterase 4 (PDE4) could bean explanation for this kind of desensitization (Giembycz M A,Phosphodiesterase 4 and tolerance to β2-adrenoceptor agonists in asthma.TiPS 17: 331-336, 1996). Therefore, the combined action of one moleculeto inhibit PDE4 activity and to activate the β2-adrenoceptor is claimedto counteract the development of tolerance to β2-adrenoceptor agonistsin vivo. In addition, such molecules with a combined mode of action willmaintain the well-known anti-inflammatory potential of PDE4 inhibitors(Torphy T J, Phosphodiesterase isozymes—molecular targets for novelantiasthma agents. Am J Respir Crit Care Med 157: 351-370, 1998), oreven make the PDE4 inhibiting component by the β2-adrenoceptor agonisticcomponent (more) effective under conditions where a PDE4 inhibitorrequires an additional cAMP trigger for its action. One example for thelatter possibility is the human eosinophil which upon stimulation bycomplement C5a does not respond to PDE4 inhibitors alone, but isinhibited in a highly synergistic fashion by the combined use of PDE4inhibitors and a β2-adrenoceptor agonist like salbutamol (Hatzelmann A,Tenor H and Schudt C, Differential effects of non-selective andselective phosphodiesterase inhibitors on human eosinophil function.Brit J Pharmacol 114: 821-831, 1995).

The compounds according to the invention have valuable pharmacologicalproperties which make them commercially utilizable. As compoundsproviding selective PDE4 inhibition combined with β2-adrenoceptoragonist activity they are suitable on the one hand as bronchialtherapeutics (for the treatment of airway obstructions on account oftheir dilating but also on account of their respiratory rate- orrespiratory drive-increasing action), but on the other hand especiallyfor the treatment of disorders, in particular of inflammatory nature,e.g. of the airways, of the skin, of the central nervous system, of theintestine, of the eyes and of the joints, which are mediated bymediators such as histamine, PAF (platelet-activating factor),arachidonic acid metabolites such as leukotrienes and prostaglandins,cytokines, interleukins, chemokines, alpha-, beta- and gamma-interferon,tumor necrosis factor (TNF) or oxygen radicals and proteases.

On account of their PDE4-inhibiting properties, the compounds accordingto the invention can be employed in human and veterinary medicine andtherapeutics, where they can be used, for example, for the treatment andprophylaxis of the following illnesses: acute and chronic (in particularinflammatory and allergen-induced) airway disorders of various origins(bronchitis, allergic bronchitis, bronchial asthma, emphysema, COPD);dermatoses (especially of proliferative, inflammatory and allergic type)such as, for example, psoriasis (vulgaris), toxic and allergic contacteczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn,pruritus in the anogenital area, alopecia areata, hypertrophic scars,discoid lupus erythematosus, follicular and wide-area pyodermias,endogenous and exogenous acne, acne rosacea and other proliferative,inflammatory and allergic skin disorders; disorders which are based onan excessive release of TNF and leukotrienes, e.g. disorders of thearthritis type (rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis and other arthritic conditions), disorders of the immunesystem (AIDS, multiple sclerosis), graft-versus-host reactions,transplant rejection reactions, symptoms of shock [septic shock,endotoxin shock, gram-negative sepsis, toxic shock syndrome and ARDS(adult respiratory distress syndrome)], and generalized inflammations inthe gastrointestinal area (Crohn's disease and ulcerative colitis);disorders which are based on allergic and/or chronic, faultyimmunological reactions in the area of the upper airways (pharynx, nose)and the adjacent regions (paranasal sinuses, eyes), such as, forexample, allergic rhinitis/sinusitis, chronic rhinitis/sinusitis,allergic conjunctivitis and nasal polyps; but also disorders of theheart which can be treated by PDE inhibitors, such as, for example,cardiac insufficiency, or disorders which can be treated on account ofthe tissue-relaxant action of the PDE inhibitors, such as, for example,erectile dysfunction or colics of the kidneys and the ureters inconnection with kidney stones. In addition, the compounds according tothe invention can be employed for the treatment of diabetes insipidusand disorders in connection with disturbances of brain metabolism, suchas, for example, cerebral senility, senile dementia (Alzheimer'sdementia), multiinfarct dementia or alternatively disorders of the CNS,such as, for example, depressions, arteriosclerotic dementia,Alzheimer's disease or multiple sclerosis.

A further subject of the invention is a process for the treatment ofmammals, including man, which are suffering from one of theabove-mentioned illnesses. The process comprises administering to thesick mammal a therapeutically efficacious and pharmacologicallytolerable amount of one or more of the compounds according to theinvention.

The invention further relates to the compounds according to theinvention for use in the treatment of mammals, including man, which aresuffering from one of the above-mentioned illnesses. The processcomprises administering to the sick mammal a therapeutically efficaciousand pharmacologically tolerable amount of one or more of the compoundsaccording to the invention.

The invention further relates to the compounds according to theinvention for use in the treatment and/or prophylaxis of illnesses, inparticular the illnesses mentioned.

The invention likewise relates to the use of the compounds according tothe invention for the production of medicaments which are employed forthe treatment and/or prophylaxis of the illnesses mentioned.

Medicaments for the treatment and/or prophylaxis of the illnessesmentioned, which contain one or more of the compounds according to theinvention, are furthermore a subject of the invention.

A further subject of the invention is a commercial product, consistingof a customary secondary pack, a primary pack containing the medicament(for example an inhaler or a blister pack) and, optionally, a packinsert, the medicament exhibiting simultaneously antagonistic actionagainst cyclic nucleotide phosphodiesterases of type 4 (PDE4) andagonistic action on β2-adrenoreceptors leading to the attenuation of thesymptoms of illnesses which are connected with cyclic nucleotidephosphodiesterases of type 4 and β2-adrenoreceptors, and the suitabilityof the medicament for the prophylaxis or treatment of illnesses whichare connected with cyclic nucleotide phosphodiesterases of the type 4and β2-adrenoreceptors being indicated on the secondary pack and/or onthe pack insert of the commercial product, and the medicament containingone or more compounds of the formula I according to the invention. Thesecondary pack, the primary pack containing the medicament and the packinsert otherwise comply with what would be regarded as standard to theperson skilled in the art for medicaments of this type.

The medicaments are prepared by processes which are known per se andfamiliar to the person skilled in the art. As medicaments, the compoundsaccording to the invention (=active compounds) are either employed assuch, or preferably in combination with suitable pharmaceuticalexcipients, e.g. in the form of tablets, coated tablets, capsules,suppositories, patches, emulsions, suspensions, gels or solutions, theactive compound content advantageously being between 0.1 and 95%.

The person skilled in the art is familiar on the basis of his/her expertknowledge with the excipients which are suitable for the desiredpharmaceutical formulations. In addition to solvents, gel-formingagents, ointment bases and other active compound vehicles, it ispossible to use, for example, antioxidants, dispersants, emulsifiers,preservatives, solubilizers, permeation promoters or complex formers.

For the treatment of disorders of the respiratory tract, the compoundsaccording to the invention are preferably also administered byinhalation.

Aerosol particles in solid, liquid or mixed composition with a diameterfrom 0.5 to 10 μm, preferably 2 to 6 μm, are preferably used, if thecompounds of the invention are administered by inhalation. The aerosolgeneration can be effected, for example, through pressure driven jetnebulizers or ultrasonic nebulizers, preferably however throughpropellant driven metered dose aerosols or through propellant free useof micronized active substances out of inhalation capsules.

Dependant on the used inhalation system the inhalation preparationscontain additional to the active substance(s) further requiredexcipients, such as propellants (for example Frigen in metered doseinhalers), surfactants, emulgators, stabilisators, preservatives,flavouring agents or fillers (for example lactose in powder inhalers).

For the purpose of inhalation a variety of devices are available withwhich aerosols with an optimal particle size can be generated andadministered in a manner highly adapted to the patients. Beside the useof adapters (Spacer, Expander) and pear-shaped containers (for exampleNebulator®, Volumatic®), as well as automatic spray burst shutter(Autohaler®) for metered dose inhalers, in particular in the field thepowder inhalers there exists a variety of technical solutions (forexample Diskhaler®, Rotadisk®, Turbohaler® or the inhaler described inEP 0 505321) with which an optimal administration of the activesubstance(s) can be achieved.

For the treatment of dermatoses, the compounds according to theinvention are in particular used in the form of those medicaments whichare suitable for topical application. For the production of themedicaments, the compounds according to the invention (=activecompounds) are preferably mixed with suitable pharmaceutical excipientsand further processed to give suitable pharmaceutical formulations.Suitable pharmaceutical formulations which may be mentioned are, forexample, powders, emulsions, suspensions, sprays, oils, ointments, fattyointments, creams, pastes, gels or solutions.

The medicaments according to the invention are prepared by methods knownper se. Dosage of the active compounds takes place in the order ofmagnitude customary for PDE inhibitors. Thus topical application forms(such as, for example, ointments) for the treatment of dermatosescontain the active compounds in a concentration of, for example,0.1-99%. The dose for administration by inhalation is customarilybetween 0.1 and 3 mg per day. The customary dose in the case of systemictherapy (p.o. or i.v.) is between 0.03 and 3 mg per kilogram per day.

Biological Investigations

In the investigation of the combined action of the compounds (PDE4inhibition and β2-adrenoceptor agonism) at the cellular level, theactivation of inflammatory cells has particular importance. As anexample, the complement C5a-induced superoxide production ofeosinophilic granulocytes may be mentioned, which can be measured asluminol-potentiated chemiluminescence (Hatzelmann A, Tenor H and SchudtC, Differential effects of non-selective and selective phosphodiesteraseinhibitors on human eosinophil function. Brit J Pharmacol 114: 821-831,1995). In this experimental setting PDE4 inhibitors by themselves areineffective unless β2-adrenoceptors are stimulated simultaneously.

The second messenger cyclic AMP (cAMP) is well-known for inhibitinginflammatory and immunocompetent cells. The PDE4 isoenzyme is broadlyexpressed in cells involved in the initiation and propagation ofinflammatory diseases (H Tenor and C Schudt, in “PhosphodiesteraseInhibitors”, 21-40, “The Handbook of Immunopharmacology”, AcademicPress, 1996), and its inhibition leads to an increase of theintracellular cAMP concentration and thus to the inhibition of cellularactivation (J E Souness et al., Immunopharmacology 47:127-162, 2000).

The antiinflammatory potential of PDE4 inhibitors in vivo in variousanimal models has been described (M M Teixeira, TIPS 18: 164-170, 1997).For the investigation of PDE4 inhibition on the cellular level (invitro), a large variety of proinflammatory responses can be measured.Examples are the superoxide production of neutrophilic (C Schudt et al.,Arch Pharmacol 344: 682-690, 1991) or eosinophilic (A Hatzelmann et al.,Brit J Pharmacol 114: 821-831, 1995) granulocytes, which can be measuredas luminol-enhanced chemiluminescence, or the synthesis of tumornecrosis factor-α in monocytes, macrophages or dendritic cells (Gantneret al., Brit J Pharmacol 121: 221-231, 1997, and Pulmonary PharmacolTherap 12: 377-386, 1999). In addition, the immunomodulatory potentialof PDE4 inhibitors is evident from the inhibition of T-cell responseslike cytokine synthesis or proliferation (D M Essayan, Biochem Pharmacol57: 965-973, 1999). Substances which inhibit the secretion of theaforementioned proinflammatory mediators are those which inhibit PDE4.The antiinflammatory action of compounds having a PDE4 inhibitorycomponent may be enhanced by the β2-adrenoceptor agonistic component inadditive or synergistic fashion.

Method for Measuring Inhibition of PDE4 Activity

PDE4 activity was determined as described by Thompson et al. (Adv CyclNucl Res 10: 69-92, 1979) with some modifications (Bauer and Schwabe,Naunyn-Schmiedeberg's Arch Pharmacol 311: 193-198, 1980). At a finalassay volume of 200 μl (96well microtiter plates) the assay mixturecontained 20 mM Tris-HCl (pH 7.4), 5 mM MgCl₂, 0.5 μM cAMP, [³H]cAMP(about 30,000 cpm/assay), the test compound and an aliquot of cytosolfrom human neutrophils which mainly contains PDE4 activity as describedby Schudt et al. (Naunyn-Schmiedeberg's Arch Pharmacol 344: 682-690,1991); the PDE3-specific inhibitor Motapizone (1 μM) was included tosuppress PDE3 activity originating from contaminating platelets.

For (some of) the examples 1-19 stock solutions of the compounds (2mmol/l) were prepared in DMSO and diluted 1:100 (v/v) in the Tris-HClbuffer mentioned above; appropriate dilutions were prepared in 1% (v/v)DMSO/Tris-HCl which were diluted 1:2 (v/v) in the assays to obtain thefinal concentrations of the inhibitors at a DMSO concentration of 0.5%(v/v) which by itself did not affect PDE activity.

To minimize problems with the solubility of the compounds, starting fromexample 20 serial dilutions of the compounds were prepared directly inDMSO and further diluted 1:100 (v/v) in the assays to obtain now thefinal concentrations of the inhibitors at a DMSO concentration of 1%(v/v) which by itself only slightly affected PDE4 activity.

After preincubation for 5 min at 37° C., the reaction was started by theaddition of substrate (cAMP) and the assays were incubated for further15 min at 37° C. 50 μl of 0.2 N HCl was added to stop the reaction andthe assays were left on ice for about 10 min. Following incubation with25 μg 5′-nucleotidase (Crotalus atrox snake venom) for 10 min at 37° C.,the assays were loaded on QAE Sephadex A-25 (1 ml bed volume). Thecolumns were eluted with 2 ml of 30 mM ammonium formiate (pH 6.0) andthe eluate was counted for radioactivity. Results were corrected forblank values (measured in the presence of denatured protein) which werebelow 5% of total radioactivity. The amount of cyclic nucleotideshydrolyzed did not exceed 30% of the original substrate concentration.The IC₅₀-values for the compounds according to the invention for theinhibition of the PDE4 activity were determined from theconcentration-inhibition curves by nonlinear-regression.

The PDE4-inhibitory values determined for the compounds according to theinvention [inhibitory concentration as −log IC₅₀ (mol/l)] follow fromTable A below, in which the numbers of the compounds correspond to thenumbers of the examples.

b) β2-Adrenoceptor Agonistic Activity in Isolated Guinea-pig Trachea

Male guinea-pigs (350-450 g) were killed by a sharp blow on the head andexsanguination, after that the trachea was removed. After clearing offadhering tissue the trachea was cut into single rings which were tiedtogether forming up to six 4- to 5-ring chains which were suspended in10-ml organ baths containing Krebs buffer of the following composition(mM): NaCl 118, KCl 5.2, CaCl₂ 1.9, MgSO₄ 0.56, NaH₂PO₄ 0.8, NaHCO₃25.0, and glucose 11.1, maintained at 37° C. and continuously aeratedwith a mixture of 95% O₂ and 5% CO₂. The end of the chain was tied atthe bottom of the tissue bath and connected to a force-displacementtransducer (Type K-30, Hugo Sachs Elektronik, Germany) for the recordingof isometric tension changes and then placed under 1.5 to 2 g oftension. After a 60 min equilibration period, during which time thepreparations were repeatedly washed and the spontaneous contractionplateaud, each tracheal preparation was pre-treated with 3×10⁻⁷ M of RP73401 for total inhibition of PDE4, which caused relaxation of thetissue between 30 and 40% of maximum (Harris et al., 1989, JPET 251:199-206). After stabilization of the relaxant response to RP 73401, thetest drugs were administered in a cumulative manner (factor 3), eachconcentration remaining in contact with the trachea until thecontractile response reached a plateau, before addition of the nexthigher concentration. At the end of the test drug administration, whichcaused maximal relaxation the tissue (verified in control experimentsfor each test drug by additional administration of 10⁻⁶ M(−)-isoprenaline), a high concentration of the β-adrenoceptorantagonist, dl-sotalol (3−6×10⁻⁴ M), was additionally given to assesswhether the relaxant response of the trachea to test compound was due toβ₂-adrenoceptor stimulation. dl-Sotalol nearly completely reversed therelaxation amplitude to the test compounds and was taken as evidence fortheir β₂-adrenoceptor agonistic property. The relaxant response to testcompound was expressed as percent determined between the relaxantamplitude after that reached by RP 73401 (0%) and the maximal relaxationobtained prior to dl-sotalol administration (100%). EC₅₀ values for ahalf-maximal relaxation of the tissue by test compound were graphicallyinterpolated from 12 to 16 individual concentration-response curve. The−log EC₅₀ values (mol/l) thus obtained were taken as a measure forβ₂-adrenoceptor agonistic activity of the test compounds.

The −log EC₅₀ values (mol/l) for the compounds according to theinvention follow from the Table A below, in which the numbers of thecompounds correspond to the numbers of the examples.

c) Inhibition of C5a-stimulated Chemiluminescence in Human Eosinophils

Eosinophils were purified essentially as described in detail elsewhere(Hatzelmann A, Tenor H and Schudt C, Differential effects ofnon-selective and selective phosphodiesterase inhibitors on humaneosinophil functions. Brit J Pharmacol 114: 821-831, 1995). Briefly,total granulocytes were first purified from blood (anticoagulated with0.3% w/v sodium citrate) by dextran sedimentation, centrifugation onFicoll Paque and hypotonic lysis of remaining red blood cells. For thefurther purification of the eosinophil fraction the magnetic cellseparation (MACS) system from Miltenyi Biotec (Bergisch-Gladbach,Germany) was applied. Eosinophils were separated from neutrophils bynegative selection using anti-CD16 microbeads in a two-step protocolusing D- and BS-(formerly called B₂-) separation columns. By this methodhuman eosinophils with a purity of >99% and a viability of >97% wereobtained.

The chemiluminescence (CL) assay was essentially performed as described(Hatzelmann et al., 1995). Briefly, measurements were performed in a“CL-buffer” (140 mM NaCl, 5 mM KCl, 1 mM MgCl₂, 10 mM HEPES, pH 7.4)containing 1 mM CaCl₂, 1 mg/ml glucose, 0.05% (w/v) BSA, 10 μM luminoland 4 μM microperoxidase (all values correspond to final concentrationsin the assays) in a total volume of 0.5 ml at a cell concentration of10⁶ cells/ml. Aliquots (0.4 ml) of the cell suspension (containingluminol and microperoxidase) were preincubated for 5 min at 37° C. inthe absence or presence of inhibitors (0.05 ml). Stock solutions of theinhibitors (10 mM) were prepared in DMSO and diluted 1:100 (v/v) inCL-buffer; subsequent dilutions were made in 1% DMSO/CL-buffer toachieve the final drug concentrations in the assays at a DMSOconcentration of 0.1% (v/v) which by itself only weakly affected the CLresponse. As a further addition (0.01 ml) during the preincubation ofthe cells salbutamol (100 nM final concentration, which by itself hardlyaffected the CL response) was included as additional cAMP trigger. Afterpreincubation, the assays were transferred into a “Multi-biolumat LB9505C” from Berthold (Wildbad, Germany) and stimulated by the additionof 0.05 ml C5a (dissolved in CL-buffer; 100 nM final concentration). CLwas continuously recorded for 1 min (C5a) and the AUC (area under thecurve) calculated. Inhibition of CL by the compounds under theseconditions is given as −log IC₃₀ (mol/l).

The inhibition of CL by the compounds according to the invention [as−log IC₃₀ (mol/l)] follow from the Table A below, in which the numbersof the compounds correspond to the number of the examples.

TABLE A Inhibition β2-Adrenoceptor Inhibition of C5a- of PDE4 agonisticstimulated chemilu- activity affinity minescence Compound [-logIC₅₀(mol/l)] [-logEC₅₀ (mol/l)] [-logIC₃₀ (mol/l)]  1 6.97 7.89 5.52  2 7.336.86 <5  3 7.47 6.77 6.52  5 8.31 6.70  6 7.69 7.60 6.00  8 8.18 6.40 117.59 8.11 6.22 12 7.65 8.61 5.92 13 7.80 6.91 6.52 14 7.43 7.24 5.30 2010.17 8.64 7.10 21 10.03 6.52 22 9.79 6.70 25 10.62 6.10 27 11.20 6.4030 10.67 6.70 32 11.40 6.64 33 10.07 6.30.

1. A compounds of formula I:

in which Ar₁ represents a phenyl radical of formula (Ia) substituted byR1 and R2 or a dihydrobenzofuranyl radical of formula (Ib) substitutedby R3, R4 and R5:

wherein R1 is hydroxyl, halogen, 1-4C-alkoxy or 1-4C-alkoxy which iscompletely or predominantly substituted by fluorine, R2 is hydroxyl,halogen, 1-8C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, or1-4C-alkoxy which is completely or predominantly substituted byfluorine, R3 is 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy,or 1-4C-alkoxy which is completely or predominantly substituted byfluorine, R4 is 1-4C-alkyl and R5 is hydrogen or 1-4C-alkyl, or whereinR4 and R5 together and with inclusion of the two carbon atoms, to whichthey are bonded, form a spiro-linked 5-, 6- or 7-membered hydrocarbonring, optionally interrupted by an oxygen or sulphur atom, R6 and R7represent independently from one another hydrogen or 14C-alkyl, or R6and R7 together and with inclusion of the two carbon atoms, to whichthey are bonded, form a group selected from:

A represents —C_(m)H_(2m)—Y—X—C_(n)H_(2n)— or—Y—X—C_(m)H_(2m)-Z-C_(n)H_(2n)—, wherein X represents a bond, —O—(oxygen), —S— (sulfur), —NH—, —C(O)—, —S(O)₂—, —C(O)—NH—, —NH—C(O)—,—C(S)—NH—, —NH—C(S)—, —NH—C(O)—NH— or —NH—C(S)—NH—, Y represents a bond,phenylene, 4-8C-cycloalkylene or azacycloalkylene, Z represents —O—,—S—, —S(O)₂—, —NH—C(O)—, —C(O)—NH—, —NH—C(S)— or —C(S)—NH—, m is aninteger from 0 to 4, n is an integer from 1 to 4, R8 is hydrogen or1-4C-alkyl, Ar₂ represents a 8-hydroxy-1H-quinolin-2-on-5-yl radical ora phenyl radical substituted by R9, R10 and R11, wherein R9 is hydrogen,halogen, hydroxyl, amino, ureido [—NH—C(O)—NH₂], formylamino[—NH—C(O)H], 1-4C-alkylcarbonylamino, di-1-4C-alkylaminocarbonyloxy,tolylcarbonyloxy [—OC(O)—C₆H₄—CH₃], hydroxymethyl,1-4C-alkylcarbonyloxy, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylsulfonylamino,1-4C-alkylsulfonylmethyl or 1-4C-alkoxy-1-4C-alkyl, R10 is hydrogen,halogen, hydroxyl, cyano, trifluoromethyl, tolylcarbonyloxy[—O—C(O)—C₆H₄—CH₃], hydroxymethyl or 1-4C-alkylcarbonyloxy, R11 ishydrogen or halogen, or a salt thereof.
 2. A compounds of formula Iaccording to claim 1 in which Ar₁ represents a phenyl radical of formula(Ia) substituted by R1 and R2 or a dihydrobenzofuranyl radical offormula (Ib) substituted by R3, R4 and R5

wherein R1 is 1-4C-alkoxy or 1-4C-alkoxy which is completely orpredominantly substituted by fluorine, R2 is 1-4C-alkoxy,3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or 1-4C-alkoxy which iscompletely or predominantly substituted by fluorine, R3 is 1-4C-alkoxy,3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or 1-4C-alkoxy which iscompletely or predominantly substituted by fluorine, R4 is 1-4C-alkyland R5 is hydrogen or 1-4C-alkyl, or wherein R4 and R5 together and withinclusion of the two carbon atoms, to which they are bonded, form aspiro-linked cyclopentane, cyclohexane, tetrahydrofuran ortetrahydropyran ring, R6 and R7 represent independently from one anotherhydrogen or 1-4C-alkyl, or R6 and R7 together and with inclusion of thetwo carbon atoms, to which they are bonded, form a group selected from:

and A either represents —C_(m)H_(2m)—Y—X—C_(n)H_(2n)—, wherein either Xrepresents a bond, Y represents a bond, m is an integer from 1 to 4, andn is an integer from 1 to 4, or X represents a bond, —O—, —S—, —C(O)—,—S(O)₂—, —C(O)—NH— or —C(S)—NH—, Y represents 1,4-phenylene,1,3-phenylene, 1,4-cyclohexylene, 1,3-cyclohexylene or1,3-cyclopentylene, m is an integer from 0 to 4, and n is an integerfrom 1 to 4, or X represents a bond, —C(O)—, —S(O)₂—, —C(O)—NH— or—C(S)—NH—, Y represents 4,1-piperidinylene, m is 0, and n is an integerfrom 1 to 4, or X represents a bond, —C(O)—, —S(O)₂—, —C(O)—NH— or—C(S)—NH—, Y represents 1,4-piperazinylene, m is an integer from 1 to 4,and n is an integer from 1 to 4, or A represents—Y—X—C_(m)H_(2m)-Z-C_(n)H_(2n)—, wherein X represents a bond, —C(O)—,—S(O)₂—, —C(O)—NH— or —C(S)—NH—, Y represents 4,1-piperidinylene, Zrepresents a bond, —O—, —S—, —S(O)₂— or —C(O)—NH—, m is an integer from1 to 4, n is an integer from 1 to 4, or X represents a bond, —O—, —S—,—C(O)—, —S(O)₂—, —C(O)—NH— or —C(S)—NH—, Y represents 1,4-phenylene,1,3-phenylene, 1,4-cyclohexylene, 1,3-cyclohexylene or1,3-cyclopentylene, Z represents a bond, —O—, —S—, —S(O)₂— or —C(O)—NH—,m is an integer from 1 to 4, and n is an integer from 1 to 4, R8 ishydrogen, methyl or ethyl, Ar₂ represents a8-hydroxy-1H-quinolin-2-on-5-yl radical or a phenyl radical substitutedby R9, R10 and R11, wherein R9 is hydrogen, halogen, hydroxyl, amino,ureido [—NH—C(O)—NH₂], formylamino [—NH—C(O)H], 1-4C-alkylcarbonylamino,di-1-4C-alkylaminocarbonyloxy, tolylcarbonyloxy [—O—C(O)—C₆H₄—CH₃],hydroxymethyl, 1-4C-alkylcarbonyloxy, 1-4C-alkyl, 1-4C-alkoxy,1-4C-alkylsulfonylamino, 1-4C-alkylsulfonylmethyl or1-4C-alkoxy-1-4C-alkyl, R10 is hydrogen, halogen, hydroxyl, cyano,trifluoromethyl, tolylcarbonyloxy [—O—C(O)—C₆H₄—CH₃], hydroxymethyl or1-4C-alkylcarbonyloxy, R11 is hydrogen or halogen, or a salt thereof. 3.A compounds of formula I according to claim 1 in which Ar₁ represents aphenyl radical of formula (Ia) substituted by R1 and R2 or adihydrobenzofuranyl radical of formula (Ib) substituted by R3, R4 andR5:

wherein R1 is 1-2C-alkoxy or 1-2C-alkoxy which is completely orpredominantly substituted by fluorine, R2 is 1-2C-alkoxy,3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or 1-2C-alkoxy which iscompletely or predominantly substituted by fluorine, R3 is 1-2C-alkoxyor 1-2C-alkoxy which is completely or predominantly substituted byfluorine, R4 is methyl and R5 is hydrogen, or wherein R4 and R5 togetherand with inclusion of the two carbon atoms, to which they are bonded,form a spiro-linked cyclopentane or cyclohexane ring, R6 and R7 togetherand with inclusion of the two carbon atoms, to which they are bonded,form a group selected from:

and A either represents —C_(m)H_(2m)—Y—X—C_(n)H_(2n)—, wherein either Xrepresents a bond, Y represents a bond, m is an integer from 1 to 4, andn is an integer from 1 to 4, or X represents a bond, —O— or —C(O)—NH—, Yrepresents 1,4-phenylene or 1,4-cyclohexylene, m is an integer from 0 to4, and n is an integer from 1 to 4, or X represents a bond, —C(O)—,—S(O)₂— or —C(S)—NH—, Y represents 4,1-piperidinylene, m is 0, and n isan integer from 1 to 4, or A represents —Y—X—C_(m)H_(2m)-Z-C_(n)H_(2n)—,wherein either X represents a bond or —C(O)—, Y represents4,1-piperidinylene, Z represents a bond, —S— or —S(O)₂—, m is an integerfrom 1 to 4, n is an integer from 1 to 4, or X represents a bond, —O— or—C(O)—NH—, Y represents 1,4-phenylene or 1,4-cyclohexylene, Z representsa bond, m is an integer from 1 to 4, and n is an integer from 1 to 4, R8is hydrogen, Ar₂ represents a 8-hydroxy-1H-quinolin-2-on-5-yl radical ora phenyl radical substituted by R9, R10 and R11, wherein R9 is hydrogen,hydroxyl or amino, R10 is hydrogen, halogen, cyano, trifluoromethyl orhydroxymethyl, R11 is hydrogen or halogen, or a salt thereof.
 4. Acompounds of formula I according to claim 1 in which Ar₁ represents aphenyl radical of formula (Ia) substituted by R1 and R2 or adihydrobenzofuranyl radical of formula (Ib) substituted by R3, R4 and R5

wherein R1 is methoxy or ethoxy, R2 is methoxy or ethoxy, R3 is methoxy,R4 and R5 together and with inclusion of the two carbon atoms, to whichthey are bonded, form a spiro-linked cyclopentane ring, R6 and R7together and with inclusion of the two carbon atoms, to which they arebonded, form a group selected from:

and A either represents —C_(m)H_(2m)—Y—X—C_(n)H_(2n)—, wherein either Xrepresents a bond, Y represents a bond, m is an integer from 1 to 4, andn is an integer from 1 to 4, or X represents a bond, —O— or —C(O)—NH—, Yrepresents 1,4-phenylene, m is an integer from 0 to 1, and n is aninteger from 1 to 4, or X represents a bond, —C(O)—, —S(O)₂— or—C(S)—NH—, Y represents 4,1-piperidinylene, m is 0, and n is an integerfrom 1 to 4, or A represents —Y—X—C_(m)H_(2m)-Z-C_(n)H_(2n)—, wherein Xrepresents a bond or —C(O)—, Y represents 4,1-piperidinylene, Zrepresents a bond, —S— or —S(O)₂—, m is 2 or 3, and n is 2 or 3, R8 ishydrogen, Ar₂ is phenyl, 4-amino-3-chloro-5-cyanophenyl,4-amino-3-chloro-5-trifluoromethylphenyl,4-hydroxy-3-hydroxymethylphenyl, 4-amino-3-cyanophenyl or4-amino-3,5-dichlorophenyl, or a salt thereof.
 5. A compounds of formulaI according to claim 1 in which Ar₁ represents a phenyl radical offormula (Ia) substituted by R1 and R2 or a dihydrobenzofuranyl radicalof formula (Ib) substituted by R3, R4 and R5

wherein R1 is hydroxyl, halogen, 1-4C-alkoxy or 1-4C-alkoxy which iscompletely or predominantly substituted by fluorine, R2 is hydroxyl,halogen, 1-8C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, or1-4C-alkoxy which is completely or predominantly substituted byfluorine, R3 is 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy,or 1-4C-alkoxy which is completely or predominantly substituted byfluorine, R4 is 1-4C-alkyl and R5 is hydrogen or 1-4C-alkyl, or whereinR4 and R5 together and with inclusion of the two carbon atoms, to whichthey are bonded, form a spiro-linked 5-, 6- or 7-membered hydrocarbonring, optionally interrupted by an oxygen or sulphur atom, R6 and R7represent independently from one another hydrogen or 1-4C-alkyl, or R6and R7 together and with inclusion of the two carbon atoms, to whichthey are bonded, form a group selected from:

A represents —(CH₂)_(m)—Y—X—(CH₂)_(n)—, wherein X represents a bond, —O—(oxygen), —S— (sulfur), —NH—, —C(O)—, —C(O)—NH— or —NH—C(O)—NH—, Yrepresents a bond, phenylene, 4-8C-cycloalkylene or azacycloalkylene, mis an integer from 0 to 4, n is an integer from 1 to 4, R8 is hydrogenor 1-4C-alkyl, Ar₂ represents a 8-hydroxy-1H-quinolin-2-on-5-yl radicalor a phenyl radical substituted by R9, R10 and R11, wherein R9 ishydrogen, halogen, hydroxyl, amino, ureido [—NH—C(O)—NH₂], formylamino[—NH—C(O)H], 1-4C-alkylcarbonylamino, di-1-4C-alkylaminocarbonyloxy,tolylcarbonyloxy [—O—C(O)—C₆H₄—CH₃], hydroxymethyl,1-4C-alkylcarbonyloxy, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylsulfonylamino,1-4C-alkylsulfonylmethyl or 1-4C-alkoxy-1-4C-alkyl, R10 is hydrogen,halogen, hydroxyl, cyano, trifluoromethyl, tolylcarbonyloxy[—O—C(O)—C₆H₄—CH₃], hydroxymethyl or 1-4C-alkylcarbonyloxy, R11 ishydrogen or halogen, or a salt thereof.
 6. A compounds of formula Iaccording to claim 1 in which Ar₁ represents a phenyl radical of formula(Ia) substituted by R1 and R2 or a dihydrobenzofuranyl radical offormula (Ib) substituted by R3, R4 and R5

wherein R1 is 1-2C-alkoxy or 1-2C-alkoxy which is completely orpredominantly substituted by fluorine, R2 is 1-2C-alkoxy,3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or 1-2C-alkoxy which iscompletely or predominantly substituted by fluorine, R3 is 1-2C-alkoxyor 1-2C-alkoxy which is completely or predominantly substituted byfluorine, R4 is methyl and R5 is hydrogen, or wherein R4 and R5 togetherand with inclusion of the two carbon atoms, to which they are bonded,form a spiro-linked cyclopentane or cyclohexane ring, R6 and R7 togetherand with inclusion of the two carbon atoms, to which they are bonded,form a group selected from:

A represents —(CH₂)_(m)—Y—X—(CH₂)_(n)—, wherein X represents a bond or—C(O)—, Y represents a bond, 1,4-phenylene, 1,4-cyclohexylene or4,1-piperidinylene, m is an integer from 0 to 4, n is an integer from 1to 4, R8 is hydrogen, Ar₂ represents a 8-hydroxy-1H-quinolin-2-on-5-ylradical or a phenyl radical substituted by R9, R10 and R11, wherein R9is hydrogen, hydroxyl or amino, R10 is hydrogen, halogen, cyano,trifluoromethyl or hydroxymethyl, R11 is hydrogen or halogen, or a saltthereof.
 7. A compounds of formula I according to claim 1 in which Ar₁represents a phenyl radical of formula (Ia) substituted by R1 and R2 ora dihydrobenzofuranyl radical of formula (Ib) substituted by R3, R4 andR5

wherein R1 is methoxy, ethoxy or difluoromethoxy, R2 is methoxy orethoxy, R3 is methoxy, R4 and R5 together and with inclusion of the twocarbon atoms, to which they are bonded, form a spiro-linked cyclopentanering, R6 and R7 together and with inclusion of the two carbon atoms, towhich they are bonded, form a group selected from:

A represents —(CH₂)_(m)—Y—X—(CH₂)_(n)—, wherein X represents a bond, Yrepresents a bond or 1,4-phenylene, m is an integer from 0 to 4, n is aninteger from 1 to 4, R8 is hydrogen, Ar₂ is phenyl,4-amino-3-chloro-5-cyanophenyl, 4-amino-3-chloro-5-trifluoromethyl,4-hydroxy-3-hydroxymethylphenyl, 4-amino-3-cyanophenyl or4-amino-3,5-dichlorphenyl, or a salt thereof.
 8. A pharmaceuticallycomposition comprising one or more compounds of formula I according toclaim 1 or a pharmaceutically acceptable salt thereof, together withpharmaceutically acceptable auxiliaries and/or carrier materials.
 9. Amethod of treating an airway disorder in a patient comprisingadministering to a patient in need thereof a therapeutically effectiveamount of one or more compounds of formula I according to claim 1 or apharmaceutically acceptable salt thereof, wherein the disease ordisorder is selected from the group consisting of bronchial asthma, COPDand allergic rhinitis.